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Robbins CJ, Bates KM, Rimm DL. HER2 testing: evolution and update for a companion diagnostic assay. Nat Rev Clin Oncol 2025:10.1038/s41571-025-01016-y. [PMID: 40195456 DOI: 10.1038/s41571-025-01016-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/13/2025] [Indexed: 04/09/2025]
Abstract
Human epidermal growth factor receptor 2 (HER2; encoded by ERBB2) testing has been a cornerstone of patient selection for HER2-targeted therapies, principally in breast cancer but also in several other solid tumours. Since the introduction of HercepTest as the original companion diagnostic for trastuzumab, HER2 assessment methods have evolved substantially, incorporating various testing modalities, from western blots, immunohistochemistry and fluorescence in situ hybridization, to early chromogenic quantitative methods and, probably in the future, fully quantitative methods. The advent of highly effective HER2-targeted antibody-drug conjugates with clinical activity at low levels of HER2 expression, such as trastuzumab deruxtecan, has necessitated the re-evaluation of HER2 testing, particularly for HER2-low tumours. In this Review, we provide an in-depth overview of the evolution of HER2 testing, the current clinical guidelines for HER2 testing across various solid tumours, challenges associated with current testing methodologies and the emerging potential of quantitative techniques. We discuss the importance of accurately defining HER2-low expression for therapeutic decision-making and how newer diagnostic approaches, such as quantitative immunofluorescence and RNA-based assays, might address the limitations of traditional immunohistochemistry-based methods. As the use of HER2-targeted therapies continues to expand to a wider range of tumour types, ensuring the precision and accuracy of HER2 testing will be crucial for guiding treatment strategies and improving patient outcomes.
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Affiliation(s)
- Charles J Robbins
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Katherine M Bates
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - David L Rimm
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
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2
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Liu M, Vathiotis I, Robbins CJ, Chan NNN, Moutafi M, Burela S, Xirou V, Schalper KA, Herbst RS, Syrigos K, Rimm DL. Quantitative Measurement of HER2 Expression in Non-Small Cell Lung Cancer With a High-Sensitivity Assay. Mod Pathol 2024; 37:100556. [PMID: 38964502 PMCID: PMC11416319 DOI: 10.1016/j.modpat.2024.100556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 06/17/2024] [Accepted: 06/26/2024] [Indexed: 07/06/2024]
Abstract
Recently, low human epidermal growth factor receptor 2 (HER2) protein expression has been proposed as a predictive biomarker for response to the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) in metastatic breast cancer. HER2 expression in non-small cell lung cancer (NSCLC) patients has never been carefully measured, and little is known about the frequency of cases with unamplified but detectable levels of the protein. Although some HER2-targeted therapies have been studied in NSCLC patients, they have been restricted to those with genomic ERBB2 gene alterations, which only represent relatively rare cases of NSCLC. Still, emerging investigations of T-DXd in NSCLC have shown promise in patients with unamplified HER2. Taken together, we hypothesize that there may be many cases of NSCLC with levels of HER2 protein expression comparable with levels seen in breast cancer that benefit from T-DXd. Here, we used a previously validated, analytic, quantitative immunofluorescence (QIF) assay that is more sensitive than legacy clinical HER2 immunohistochemistry assays. We measured HER2 protein levels in NSCLC cases to determine the proportion of cases with detectable HER2 expression. Using cell line calibration microarrays alongside our QIF method enabled us to convert HER2 signal into units of attomoles per mm2. We found that over 63% of the 741 analyzed NSCLC cases exhibited HER2 expression above the limit of detection, with more than 17% of them exceeding the lower limit of quantification. Although the threshold for response to T-DXd in breast cancer is still unknown, many cases of NSCLC have expression in a range comparable to breast cancer cases with immunohistochemistry scores of 1+ or 2+. Our assay could potentially select NSCLC cases with a detectable target (ie, HER2) that might benefit from HER2 antibody-drug conjugates, irrespective of ERBB2 genomic alterations.
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MESH Headings
- Humans
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/pathology
- Carcinoma, Non-Small-Cell Lung/metabolism
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Lung Neoplasms/pathology
- Lung Neoplasms/genetics
- Lung Neoplasms/drug therapy
- Lung Neoplasms/metabolism
- Receptor, ErbB-2/analysis
- Receptor, ErbB-2/genetics
- Receptor, ErbB-2/metabolism
- Biomarkers, Tumor/analysis
- Biomarkers, Tumor/genetics
- Female
- Aged
- Middle Aged
- Male
- Trastuzumab/therapeutic use
- Antineoplastic Agents, Immunological/therapeutic use
- Immunoconjugates/therapeutic use
- Camptothecin/analogs & derivatives
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Affiliation(s)
- Matthew Liu
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
| | - Ioannis Vathiotis
- Department of Medicine, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Charles J Robbins
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
| | - Nay Nwe Nyein Chan
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
| | - Myrto Moutafi
- Department of Medicine, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Sneha Burela
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
| | - Vasiliki Xirou
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
| | - Kurt A Schalper
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
| | - Roy S Herbst
- Department of Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Konstantinos Syrigos
- Department of Medicine, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - David L Rimm
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut; Department of Medicine, Yale University School of Medicine, New Haven, Connecticut.
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3
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Jeon JH, Woo Kim S, Kim YJ, Park JW, Eun Moon J, Beom Lee Y, Yu H, Lee GH, Jin SH, Jeong JH. Synthesis and evaluation of antibody-drug conjugates with high drug-to-antibody ratio using dimaleimide-DM1 as a linker- payload. Bioorg Chem 2024; 149:107504. [PMID: 38850783 DOI: 10.1016/j.bioorg.2024.107504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 05/22/2024] [Accepted: 05/27/2024] [Indexed: 06/10/2024]
Abstract
The notable characteristics of recently emerged Antibody-Drug Conjugates (ADCs) encompass the targeting of Human Epidermal growth factor Receptor 2 (HER2) through monoclonal antibodies (mAbs) and a high ratio of drug to antibody (DAR). The achievements of Kadcyla® (T-DM1) and Enhertu® (T-Dxd) have demonstrated that HER2-targeting antibodies, such as trastuzumab, have shown to be competitive in terms of efficacy and price for development. Furthermore, with the arrival of T-Dxd and Trodelvy®, high-DAR (7-8) ADCs, which differ from the moderate DAR (3-4) ADCs that were formerly regarded as conventional, are being acknowledged for their worth. Following this trend of drug development, we endeavored to develop a high-DAR ADC using a straightforward approach involving the utilization of DM1, a highly potent substance, in combination with the widely recognized trastuzumab. To achieve a high DAR, DM1 was conjugated to reduced cysteine through the simple design and synthesis of various dimaleimide linkers with differing lengths. Using LC and MS analysis, we have demonstrated that our synthesis methodology is uncomplicated and efficacious, yielding trastuzumab-based ADCs that exhibit a remarkable degree of uniformity. These ADCs have been experimentally substantiated to exert an inhibitory effect on cancer cells in vitro, thus affirming their value as noteworthy additions to the realm of ADCs.
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Affiliation(s)
- Joo-Hyun Jeon
- AbchemBio co., Ltd., D 111, Veritas Hall, Yonsei University, 85 Songdogqahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea; College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea
| | - Seo Woo Kim
- AbchemBio co., Ltd., D 111, Veritas Hall, Yonsei University, 85 Songdogqahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea
| | - Yoon-Jung Kim
- AbchemBio co., Ltd., D 111, Veritas Hall, Yonsei University, 85 Songdogqahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea
| | - Jang-Woo Park
- AbchemBio co., Ltd., D 111, Veritas Hall, Yonsei University, 85 Songdogqahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea; College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea
| | - Jee Eun Moon
- AbchemBio co., Ltd., D 111, Veritas Hall, Yonsei University, 85 Songdogqahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea
| | - Yong Beom Lee
- AbchemBio co., Ltd., D 111, Veritas Hall, Yonsei University, 85 Songdogqahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea
| | - Hana Yu
- AbchemBio co., Ltd., D 111, Veritas Hall, Yonsei University, 85 Songdogqahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea
| | - Geon-Ho Lee
- AbchemBio co., Ltd., D 111, Veritas Hall, Yonsei University, 85 Songdogqahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea
| | - Sung-Ha Jin
- AbchemBio co., Ltd., D 111, Veritas Hall, Yonsei University, 85 Songdogqahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea.
| | - Jin-Hyun Jeong
- AbchemBio co., Ltd., D 111, Veritas Hall, Yonsei University, 85 Songdogqahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea; College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea.
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Sayin AZ, Abali Z, Senyuz S, Cankara F, Gursoy A, Keskin O. Conformational diversity and protein-protein interfaces in drug repurposing in Ras signaling pathway. Sci Rep 2024; 14:1239. [PMID: 38216592 PMCID: PMC10786864 DOI: 10.1038/s41598-023-50913-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 12/27/2023] [Indexed: 01/14/2024] Open
Abstract
We focus on drug repurposing in the Ras signaling pathway, considering structural similarities of protein-protein interfaces. The interfaces formed by physically interacting proteins are found from PDB if available and via PRISM (PRotein Interaction by Structural Matching) otherwise. The structural coverage of these interactions has been increased from 21 to 92% using PRISM. Multiple conformations of each protein are used to include protein dynamics and diversity. Next, we find FDA-approved drugs bound to structurally similar protein-protein interfaces. The results suggest that HIV protease inhibitors tipranavir, indinavir, and saquinavir may bind to EGFR and ERBB3/HER3 interface. Tipranavir and indinavir may also bind to EGFR and ERBB2/HER2 interface. Additionally, a drug used in Alzheimer's disease can bind to RAF1 and BRAF interface. Hence, we propose a methodology to find drugs to be potentially used for cancer using a dataset of structurally similar protein-protein interface clusters rather than pockets in a systematic way.
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Affiliation(s)
- Ahenk Zeynep Sayin
- Department of Chemical and Biological Engineering, College of Engineering, Koc University, Rumeli Feneri Yolu Sariyer, 34450, Istanbul, Turkey
| | - Zeynep Abali
- Graduate School of Science and Engineering, Computational Sciences and Engineering, Koc University, 34450, Istanbul, Turkey
| | - Simge Senyuz
- Graduate School of Science and Engineering, Computational Sciences and Engineering, Koc University, 34450, Istanbul, Turkey
| | - Fatma Cankara
- Graduate School of Science and Engineering, Computational Sciences and Engineering, Koc University, 34450, Istanbul, Turkey
| | - Attila Gursoy
- Department of Computer Engineering, Koc University, 34450, Istanbul, Turkey
| | - Ozlem Keskin
- Department of Chemical and Biological Engineering, College of Engineering, Koc University, Rumeli Feneri Yolu Sariyer, 34450, Istanbul, Turkey.
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Mercanoglu B, Karstens KF, Giannou AD, Meiners J, Lücke J, Seeger P, Brackrock V, Güngör C, Izbicki JR, Bockhorn M, Hackert T, Melling N, Wolters-Eisfeld G. A Comprehensive Analysis of Tn and STn Antigen Expression in Esophageal Adenocarcinoma. Cancers (Basel) 2024; 16:240. [PMID: 38254730 PMCID: PMC10814236 DOI: 10.3390/cancers16020240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 12/29/2023] [Accepted: 01/02/2024] [Indexed: 01/24/2024] Open
Abstract
Differential glycosylation, marked by the presence of truncated O-glycans, is a distinctive feature of epithelial-derived cancers. However, there is a notable gap in research regarding the expression of Tn and STn antigens in esophageal adenocarcinoma (EAC). To address this, we employed commercially available antibodies, previously validated for Tn and STn antigens, to analyze two cohorts of EAC tissues. Initially, large-area tissue sections from formalin-fixed paraffin-embedded (FFPE) EAC and corresponding healthy tissues were subjected to immunohistochemistry (IHC) staining and scoring. Subsequently, we evaluated the RNA expression levels of crucial O-glycosylation related genes-C1GALT1 and C1GALT1C1-using a quantitative real-time polymerase chain reaction (qRT-PCR). In a comprehensive analysis, a substantial cohort of EAC tissues (n = 311 for Tn antigen, n = 351 for STn antigen) was investigated and correlated with clinicopathological data. Our findings revealed that Tn and STn antigens are highly expressed (approximately 71% for both) in EAC, with this expression being tumor-specific. Notably, Tn antigen expression correlates significantly with the depth of tumor cell infiltration (p = 0.026). These antigens emerge as valuable markers and potential therapeutic targets for esophageal adenocarcinoma.
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Affiliation(s)
- Baris Mercanoglu
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany (A.D.G.); (J.L.); (C.G.); (J.R.I.); (M.B.); (T.H.); (N.M.)
| | - Karl-Frederick Karstens
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany (A.D.G.); (J.L.); (C.G.); (J.R.I.); (M.B.); (T.H.); (N.M.)
| | - Anastasios D. Giannou
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany (A.D.G.); (J.L.); (C.G.); (J.R.I.); (M.B.); (T.H.); (N.M.)
- Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Jan Meiners
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany (A.D.G.); (J.L.); (C.G.); (J.R.I.); (M.B.); (T.H.); (N.M.)
- Department of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Jöran Lücke
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany (A.D.G.); (J.L.); (C.G.); (J.R.I.); (M.B.); (T.H.); (N.M.)
- Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Philipp Seeger
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany (A.D.G.); (J.L.); (C.G.); (J.R.I.); (M.B.); (T.H.); (N.M.)
| | - Vera Brackrock
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany (A.D.G.); (J.L.); (C.G.); (J.R.I.); (M.B.); (T.H.); (N.M.)
| | - Cenap Güngör
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany (A.D.G.); (J.L.); (C.G.); (J.R.I.); (M.B.); (T.H.); (N.M.)
| | - Jakob R. Izbicki
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany (A.D.G.); (J.L.); (C.G.); (J.R.I.); (M.B.); (T.H.); (N.M.)
| | - Maximilian Bockhorn
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany (A.D.G.); (J.L.); (C.G.); (J.R.I.); (M.B.); (T.H.); (N.M.)
- Department of General and Visceral Surgery, University Medical Center Oldenburg, 26133 Oldenburg, Germany
| | - Thilo Hackert
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany (A.D.G.); (J.L.); (C.G.); (J.R.I.); (M.B.); (T.H.); (N.M.)
| | - Nathaniel Melling
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany (A.D.G.); (J.L.); (C.G.); (J.R.I.); (M.B.); (T.H.); (N.M.)
| | - Gerrit Wolters-Eisfeld
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany (A.D.G.); (J.L.); (C.G.); (J.R.I.); (M.B.); (T.H.); (N.M.)
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Skórzewska M, Gęca K, Polkowski WP. A Clinical Viewpoint on the Use of Targeted Therapy in Advanced Gastric Cancer. Cancers (Basel) 2023; 15:5490. [PMID: 38001751 PMCID: PMC10670421 DOI: 10.3390/cancers15225490] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 11/05/2023] [Accepted: 11/17/2023] [Indexed: 11/26/2023] Open
Abstract
The development of therapies for advanced gastric cancer (GC) has made significant progress over the past few years. The identification of new molecules and molecular targets is expanding our understanding of the disease's intricate nature. The end of the classical oncology era, which relied on well-studied chemotherapeutic agents, is giving rise to novel and unexplored challenges, which will cause a significant transformation of the current oncological knowledge in the next few years. The integration of established clinically effective regimens in additional studies will be crucial in managing these innovative aspects of GC. This study aims to present an in-depth and comprehensive review of the clinical advancements in targeted therapy and immunotherapy for advanced GC.
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7
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Yasar HA. Genomic Variations in Esophageal Squamous Cell Carcinoma and Esophageal Adenocarcinoma. Cureus 2023; 15:e45689. [PMID: 37745740 PMCID: PMC10512880 DOI: 10.7759/cureus.45689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/21/2023] [Indexed: 09/26/2023] Open
Abstract
Objectives Using a comprehensive dataset derived from the American Association for Cancer Research (AACR) Project Genomics, Evidence, Neoplasia, Information, and Exchange (GENIE), we sought to demonstrate the genetic characteristics of esophageal squamous cell cancer (ESCC) and esophageal adenocarcinoma (EAC). Methodology Data were extracted from cBioPortal for cancer genomics (genie.cbioportal.org). Patients with EAC and squamous cell carcinoma were selected. To compare categorical variables, either the chi-square or Kruskal-Wallis test was used. The Benjamini-Hochberg method was applied to correct P-values, and consequently, false discovery rate-adjusted q-values were computed. When the q-value was <0.05, the P-value < 0.05 was accepted as statistically significant. Results In this study, 1,381 patients with EAC and 312 patients with ESCC were analyzed. Gene alterations were different between the two groups. In EAC, genetic alterations were detected in ERBB2, KRAS, SMAD4, and TACC3 genes, whereas ESCC exhibited alterations in CCDN1, NFE2L2, FGF19, FGF3, FGF4, NOTCH1, and CDKN2B genes. Conclusions Notably, this study showed distinct differences in gene alterations between ESCC and EAC, thereby enhancing our understanding of the genetic landscape of these tumors. Further research is required to elucidate the functional implications of these genetic variations to develop targeted therapies that can improve the prognosis of patients with esophageal cancer.
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Affiliation(s)
- Hatime A Yasar
- Medical Oncology, Ankara University School of Medicine, Ankara, TUR
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Abu Al Karsaneh O, Al Anber A, ALQudah M, Al-Mustafa S, AlMa'aitah H, Sughayer M. Prevalence and clinicopathological associations of HER2 expression in non-small cell lung cancer: a retrospective study in Jordanian patients. Diagn Pathol 2023; 18:75. [PMID: 37340403 DOI: 10.1186/s13000-023-01364-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Accepted: 06/12/2023] [Indexed: 06/22/2023] Open
Abstract
BACKGROUND Human epidermal growth factor receptor 2 (HER2), a promising therapeutic target, can be mutated, amplified, or overexpressed in different malignancies, including non-small cell lung cancer (NSCLC). Although these alterations showed adverse prognostic effects in many cancers, their clinical significance in NSCLC is controversial. This study primarily assessed the prevalence of HER2 protein expression in NSCLC among Jordanian patients. In addition, the possible association between HER2 protein expression and clinicopathological variables was evaluated. METHODS A total of 100 surgically resected NSCLC cases treated at King Hussein Cancer Center (KHCC) between 2009 and 2021 were examined for HER2 protein expression using immunohistochemistry (IHC). The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines for breast cancer were applied to interpret the results with a final score ranging from 0 to 3+, considering a score of 3 + as overexpression. Additionally, a separate subset of patients was tested for HER2 gene mutation. Fisher's exact test was used to assess the association between HER2 scores and the other variables. Kaplan-Meier method was used to calculate survival. RESULTS Of the 100 cases, Her2 overexpression (score 3+) was detected in 2 cases (2%), score 2 + in 10 cases (10%), score 1 + in 12 cases (12%), and score 0 in 76 cases (76%). The two positive cases were one adenocarcinoma and one squamous cell carcinoma; both patients were elderly male smokers. No significant association was identified between Her2 expression and age, gender, smoking, histological subtype, grade, stage, tumor size, and lymph node status. Our findings also showed no association between Her2 expression and survival; however, advanced tumor stages and positive lymph node metastasis were significantly associated with poor overall survival. All cases tested for the Her2 mutation were negative. CONCLUSIONS Her2 overexpression is uncommon in NSCLC among the Jordanian population. However, when the same scoring criteria are used, the rates are similar to other results found in Asian cohorts. Due to our study's relatively small sample size, a larger one is required to investigate the prognostic value and the molecular associations between the different Her2 alterations.
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Affiliation(s)
- Ola Abu Al Karsaneh
- Department of Microbiology, Pathology and Forensic Medicine, Faculty of Medicine, The Hashemite University, Zarqa, 13133, Jordan
| | - Arwa Al Anber
- Department of Pharmacology and Public Health, Faculty of Medicine, The Hashemite University, Zarqa, 13133, Jordan
| | - Mohammad ALQudah
- Department of Microbiology, Pathology and Forensic Medicine, Faculty of Medicine, The Hashemite University, Zarqa, 13133, Jordan
| | - Sahar Al-Mustafa
- Department of Pathology and Laboratory Medicine, King Hussein Cancer Center, Amman, Jordan
| | - Hussien AlMa'aitah
- Department of Pathology and Laboratory Medicine, King Hussein Cancer Center, Amman, Jordan
| | - Maher Sughayer
- Department of Pathology and Laboratory Medicine, King Hussein Cancer Center, Amman, Jordan.
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9
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Lumish MA, Maron SB, Paroder V, Chou JF, Capanu M, Philemond S, O'Donoghue JA, Schöder H, Lewis JS, Lyashchenko SK, Pandit-Taskar N, Janjigian YY. Noninvasive Assessment of Human Epidermal Growth Factor Receptor 2 (HER2) in Esophagogastric Cancer Using 89Zr-Trastuzumab PET: A Pilot Study. J Nucl Med 2023; 64:724-730. [PMID: 36418168 PMCID: PMC10152123 DOI: 10.2967/jnumed.122.264470] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 11/08/2022] [Accepted: 11/08/2022] [Indexed: 11/25/2022] Open
Abstract
Variations in human epidermal growth factor receptor 2 (HER2) expression between the primary tumor and metastases may contribute to drug resistance in HER2-positive (HER2+) metastatic esophagogastric cancer (mEGC). 89Zr-trastuzumab PET (HER2 PET) holds promise for noninvasive assessment of variations in HER2 expression and target engagement. The aim of this study was to describe HER2 PET findings in patients with mEGC. Methods: Patients with HER2+ mEGC were imaged with HER2 PET, 18F-FDG PET, and CT. Lesions were annotated using measurements (on CT) and maximum SUVs (on HER2 PET). Correlation of visualized disease burden among imaging modalities with clinical and pathologic characteristics was performed. Results: Thirty-three patients with HER2+ mEGC were imaged with HER2 PET and CT (12% esophageal, 64% gastroesophageal junction, and 24% gastric adenocarcinoma), 26 of whom were also imaged with 18F-FDG PET. More lesions were identified on 18F-FDG PET (median, 7 [range, 1-14]) than HER2 PET (median, 4 [range, 0-11]). Of the 8 lesions identified on HER2 but not on 18F-FDG PET, 3 (38%) were in bone and 1 was in the brain. Of the 68 lesions identified on 18F-FDG but not on HER2 PET, 4 (6%) were in bone and the remainder were in the lymph nodes (35, 51%) and liver (16, 24%). Of the 33 total patients, 23 (70%) were HER2 imaging-positive (≥50% of tumor load positive). Only 10 patients had 100% of the tumor load positive; 2 had 0% positive. When only patients receiving HER2-directed therapy as first-line treatment were considered (n = 13), median progression-free survival (PFS) therapy was not significantly different between HER2 imaging-positive and -negative patients. Median PFS for patients with at least 1 intense or very intense lesion (SUV ≥ 10) was 16 (95% CI: 11-not reached) mo (n = 7), compared with 12 (95% CI: 6.3-not reached) mo for patients without an intense or very intense lesion (n = 6) (P = 0.35). Conclusion: HER2 PET may identify heterogeneity of HER2 expression and allow assessment of lesions throughout the entire body. A potential application of HER2 PET is noninvasive evaluation of HER2 status including assessment of intrapatient disease heterogeneity not captured by standard imaging or single-site biopsies.
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Affiliation(s)
- Melissa A Lumish
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York;
- Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Steven B Maron
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Viktoriya Paroder
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Joanne F Chou
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Marinela Capanu
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Steven Philemond
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Joseph A O'Donoghue
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Heiko Schöder
- Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jason S Lewis
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York
- Radiochemistry and Molecular Imaging Probes Core, Memorial Sloan Kettering Cancer Center, New York, New York and
| | - Serge K Lyashchenko
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York
- Radiochemistry and Molecular Imaging Probes Core, Memorial Sloan Kettering Cancer Center, New York, New York and
| | - Neeta Pandit-Taskar
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York;
- Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Radiology, Weill Cornell Medical College, New York, New York
| | - Yelena Y Janjigian
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Medicine, Weill Cornell Medical College, New York, New York
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10
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Collins SJ, Guo J, Rizzo RC, Miller WT. Inhibition of mutationally activated HER2. Chem Biol Drug Des 2023; 101:87-102. [PMID: 36029027 PMCID: PMC9879383 DOI: 10.1111/cbdd.14125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 06/24/2022] [Accepted: 07/30/2022] [Indexed: 01/28/2023]
Abstract
Human epidermal growth factor receptor 2 (HER2) is an oncogenic driver and key therapeutic target for human cancers. Current therapies targeting HER2 are primarily based on overexpression of the wild-type form of HER2. However, kinase domain mutations have been identified that can increase the activity of HER2 even when expressed at basal levels. Using purified enzymes, we confirmed the hyperactivity of two HER2 mutants (D769Y and P780insGSP). To identify small molecule inhibitors against these cancer-associated variants, we used a combined approach consisting of biochemical testing, similarity-based searching, and in silico modeling. These approaches resulted in the identification of a candidate molecule that inhibits mutant forms of HER2 in vitro and in cell-based assays. Our structural model predicts that the compound takes advantage of water-mediated interactions in the HER2 kinase binding pocket.
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Affiliation(s)
- Stephen J. Collins
- Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York, USA
| | - Jiaye Guo
- Department of Applied Mathematics & Statistics, Stony Brook University, Stony Brook, New York, USA
| | - Robert C. Rizzo
- Department of Applied Mathematics & Statistics, Stony Brook University, Stony Brook, New York, USA,Laufer Center for Physical & Quantitative Biology, Stony Brook University, Stony Brook, New York, USA,Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, New York, USA
| | - W. Todd Miller
- Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York, USA,Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, New York, USA,Department of Veterans Affairs Medical Center, Northport, New York, USA
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11
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He S, Xu J, Liu X, Zhen Y. Advances and challenges in the treatment of esophageal cancer. Acta Pharm Sin B 2021; 11:3379-3392. [PMID: 34900524 PMCID: PMC8642427 DOI: 10.1016/j.apsb.2021.03.008] [Citation(s) in RCA: 160] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 01/24/2021] [Accepted: 02/06/2021] [Indexed: 12/18/2022] Open
Abstract
Esophageal cancer (EC) is one of the most common cancers with high morbidity and mortality rates. EC includes two histological subtypes, namely esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). ESCC primarily occurs in East Asia, whereas EAC occurs in Western countries. The currently available treatment strategies for EC include surgery, chemotherapy, radiation therapy, molecular targeted therapy, and combinations thereof. However, the prognosis remains poor, and the overall five-year survival rate is very low. Therefore, achieving the goal of effective treatment remains challenging. In this review, we discuss the latest developments in chemotherapy and molecular targeted therapy for EC, and comprehensively analyze the application prospects and existing problems of immunotherapy. Collectively, this review aims to provide a better understanding of the currently available drugs through in-depth analysis, promote the development of new therapeutic agents, and eventually improve the treatment outcomes of patients with EC.
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Affiliation(s)
- Shiming He
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China
| | - Jian Xu
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China
| | - Xiujun Liu
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China
| | - Yongsu Zhen
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China
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12
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Grieb BC, Agarwal R. HER2-Directed Therapy in Advanced Gastric and Gastroesophageal Adenocarcinoma: Triumphs and Troubles. Curr Treat Options Oncol 2021; 22:88. [PMID: 34424404 PMCID: PMC8436174 DOI: 10.1007/s11864-021-00884-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/23/2021] [Indexed: 01/22/2023]
Abstract
OPINION STATEMENT Gastric and gastroesophageal junction (GEJ) cancers represent the third leading cause of malignancy-associated death worldwide. Approximately 15-20% of these adenocarcinomas overexpress the human epidermal growth factor receptor 2 (HER2), a pro-proliferative receptor tyrosine kinase that has been therapeutically exploited in other disease contexts. The landmark ToGA trial demonstrated that trastuzumab, an anti-HER2 antibody, could improve overall survival for patients with HER2 overexpressing advanced gastric and GEJ adenocarcinomas. In the ensuing decade, great effort has been made to refine and expand this therapeutic strategy through a variety of avenues including optimization of chemotherapy backbones, identifying potential synergy with immune checkpoint inhibition, deployment of alternative HER2-targeted antibodies, use of small molecule inhibitors, and development of HER2-directed antibody drug conjugates. While the results of these efforts have had variable success, they have led to a greater understanding of the mechanisms of both primary and acquired resistance to HER2-directed therapies, laying the groundwork for future investigations. Recently, KEYNOTE-811 and DESTINY-Gastric01 have led to the FDA approvals of pembrolizumab in combination with trastuzumab and chemotherapy in the 1st-line advanced setting and trastuzumab deruxtecan (fam-trastuzumab deruxtecan-nxki) in the 2nd-line setting, respectively. Herein, we review these significant works as well as discuss the ongoing investigations they have inspired, which aim to find and utilize additional means for targeting HER2 in gastric and GEJ cancers.
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Affiliation(s)
- Brian C Grieb
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
| | - Rajiv Agarwal
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
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13
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Nguyen TH, Vemu PL, Hoy GE, Boudjadi S, Chatterjee B, Shern JF, Khan J, Sun W, Barr FG. Serine hydroxymethyltransferase 2 expression promotes tumorigenesis in rhabdomyosarcoma with 12q13-q14 amplification. J Clin Invest 2021; 131:e138022. [PMID: 34166228 DOI: 10.1172/jci138022] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 06/16/2021] [Indexed: 12/11/2022] Open
Abstract
The 12q13-q14 chromosomal region is recurrently amplified in 25% of fusion-positive (FP) rhabdomyosarcoma (RMS) cases and is associated with a poor prognosis. To identify amplified oncogenes in FP RMS, we compared the size, gene composition, and expression of 12q13-q14 amplicons in FP RMS with those of other cancer categories (glioblastoma multiforme, lung adenocarcinoma, and liposarcoma) in which 12q13-q14 amplification frequently occurs. We uncovered a 0.2 Mb region that is commonly amplified across these cancers and includes CDK4 and 6 other genes that are overexpressed in amplicon-positive samples. Additionally, we identified a 0.5 Mb segment that is only recurrently amplified in FP RMS and includes 4 genes that are overexpressed in amplicon-positive RMS. Among these genes, only serine hydroxymethyltransferase 2 (SHMT2) was overexpressed at the protein level in an amplicon-positive RMS cell line. SHMT2 knockdown in amplicon-positive RMS cells suppressed growth, transformation, and tumorigenesis, whereas overexpression in amplicon-negative RMS cells promoted these phenotypes. High SHMT2 expression reduced sensitivity of FP RMS cells to SHIN1, a direct SHMT2 inhibitor, but sensitized cells to pemetrexed, an inhibitor of the folate cycle. In conclusion, our study demonstrates that SHMT2 contributes to tumorigenesis in FP RMS and that SHMT2 amplification predicts differential response to drugs targeting this metabolic pathway.
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Affiliation(s)
| | | | | | | | | | | | - Javed Khan
- Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
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14
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HER2 Protein Overexpression and Gene Amplification in Tubo-Ovarian High-grade Serous Carcinomas. Int J Gynecol Pathol 2021; 41:313-319. [PMID: 34320531 DOI: 10.1097/pgp.0000000000000812] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Most tubo-ovarian high-grade serous carcinomas (TO-HGSC) are diagnosed in advanced stages. Although the majority of patients achieve initial remission with cytoreductive surgery and chemotherapy, mortality rate remains high due to recurrent/progressive disease. The addition of trastuzumab to carboplatin-paclitaxel improved progression-free survival of patients with human epidermal growth factor receptor 2 (HER2)-positive uterine serous carcinoma. After this encouraging result of transtuzumab in HER2-positive uterine serous carcinoma, we aimed to determine the frequency of HER2 overexpression/amplification in TO-HGSC and reveal the utility of 2018 ASCO/CAP HER2 testing guideline in breast cancer for TO-HGSC. For 100 cases, HER2 protein expression was assessed by immunohistochemistry and scored from 0 to 3+ according to 2018 ASCO/CAP HER2 testing guideline. HER2 gene amplification was assessed by florescence in situ hybridization for all the 2+ and 3+ cases as well as 5 of the 0/1+ cases. Among 100 cases, immunohistochemistry scores were 0/1+ in 81 cases, 2+ in 18 cases and 3+ in 1 case. By florescence in situ hybridization, the only 3+ case and 1 of the 2+ cases were HER2-amplified and all 5 of the 0/1+ cases were HER2 nonamplified. Subclonal HER2 overexpression/amplification was identified in 1 of the neoadjuvant cases comprising <10% of the entire tumor. In summary, HER2 overexpression/amplification was found in 2% of TO-HGSC. The 2018 ASCO/CAP HER2 testing guideline in breast cancer can be utilized for TO-HGSC. Future studies are needed to explore HER2-targeted therapies in TO-HGSC and expand the patient population who may benefit from HER2-targeted therapies such as patients with activating mutations in HER2 gene without overexpression/amplification.
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15
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McShane R, Arya S, Stewart AJ, Caie P, Bates M. Prognostic features of the tumour microenvironment in oesophageal adenocarcinoma. Biochim Biophys Acta Rev Cancer 2021; 1876:188598. [PMID: 34332022 DOI: 10.1016/j.bbcan.2021.188598] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 07/26/2021] [Accepted: 07/26/2021] [Indexed: 12/12/2022]
Abstract
Oesophageal adenocarcinoma (OAC) is a disease with an incredibly poor survival rate and a complex makeup. The growth and spread of OAC tumours are profoundly influenced by their surrounding microenvironment and the properties of the tumour itself. Constant crosstalk between the tumour and its microenvironment is key to the survival of the tumour and ultimately the death of the patient. The tumour microenvironment (TME) is composed of a complex milieu of cell types including cancer associated fibroblasts (CAFs) which make up the tumour stroma, endothelial cells which line blood and lymphatic vessels and infiltrating immune cell populations. These various cell types and the tumour constantly communicate through environmental cues including fluctuations in pH, hypoxia and the release of mitogens such as cytokines, chemokines and growth factors, many of which help promote malignant progression. Eventually clusters of tumour cells such as tumour buds break away and spread through the lymphatic system to nearby lymph nodes or enter the circulation forming secondary metastasis. Collectively, these factors need to be considered when assessing and treating patients clinically. This review aims to summarise the ways in which these various factors are currently assessed and how they relate to patient treatment and outcome at an individual level.
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Affiliation(s)
| | - Swati Arya
- School of Medicine, University of St Andrews, Fife, UK
| | | | - Peter Caie
- School of Medicine, University of St Andrews, Fife, UK
| | - Mark Bates
- Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, St James's Hospital, Dublin 8, Ireland.
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Jimenez-Fonseca P, Carmona-Bayonas A, Martinez-Torron A, Alsina M, Custodio A, Serra O, Cacho Lavin D, Limón ML, Sauri T, López F, Visa L, Granja M, Martínez Lago N, Arrazubi V, Vidal Tocino R, Hernandez R, Aguado G, Cano JM, Martín Carnicero A, Mangas M, Pimentel P, Fernández Montes A, Macias Declara I, Longo F, Ramchandani A, Martín Richard M, Hurtado A, Azkarate A, Hernández Pérez C, Serrano R, Gallego J. External validity of clinical trials with diverse trastuzumab-based chemotherapy regimens in advanced gastroesophageal adenocarcinoma: data from the AGAMENON-SEOM registry. Ther Adv Med Oncol 2021; 13:17588359211019672. [PMID: 34211587 PMCID: PMC8216357 DOI: 10.1177/17588359211019672] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 04/29/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Trastuzumab combined with cisplatin and fluoropyrimidines, either capecitabine or 5-fluorouracile (XP/FP), is the standard first-line treatment for advanced, HER2-positive, gastric cancer patients based on the ToGA trial. Despite the lack of phase III trials, many clinicians administer trastuzumab with alternative regimens. One meta-analysis suggests that substituting cisplatin for oxaliplatin might lead to greater efficacy and less toxicity. METHODS 594 patients with HER2-positive gastroesophageal adenocarcinoma were recruited from the AGAMENON-SEOM registry. The objective was to evaluate the external validity of clinical trials with chemotherapy and trastuzumab. RESULTS The regimens used in at least 5% of the patients were XP (27%), oxaliplatin and capecitabine (CAPOX) (26%), oxaliplatin and 5-fluorouracil (FOLFOX) (14%), FP (14%), triplet with anthracycline/docetaxel (7%), and carboplatin-FU (5%). Median exposure to trastuzumab was longer with FOLFOX (11.4 months, 95% CI, 9.1-21.0) versus ToGA regimens (7.5, 6.4-8.5), p < 0.001. Patients with HER2-IHC 3+ cancers had higher response rates than those with IHC 2+/FISH+, odds-ratio 1.97 (95% CI, 1.25-3.09). The results achieved with CAPOX-trastuzumab were comparable to those attained with ToGA regimens. FOLFOX-trastuzumab was superior to ToGA schemes in terms of overall survival (OS), with a greater magnitude of effect in IHC 2+/FISH+ tumors (HR 0.47, 0.24-0.92) compared with IHC 3+ (HR 0.69, 0.49-0.96), and in diffuse (HR 0.37, 0.20-0.69) versus intestinal-type tumors (HR 0.76, 0.54-1.06). CONCLUSION We have updated the external validity of clinical trials with trastuzumab in first-line treatment of gastric cancer. Our data confirm the comparable outcomes of ToGA regimens and CAPOX-trastuzumab in clinical practice and point toward a possible benefit of FOLFOX-trastuzumab, contingent on the subtypes typically less sensitive to trastuzumab, to be confirmed in clinical trials.
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Affiliation(s)
- Paula Jimenez-Fonseca
- Medical Oncology Department, Hospital Universitario Central de Asturias, ISPA, Oviedo, Spain
| | - Alberto Carmona-Bayonas
- Medical Oncology Department, Hospital Universitario Morales Meseguer, Calle Marqués de los Vélez, s/n, Murcia, 30007, Spain
| | - Alba Martinez-Torron
- Pharmacy Department, Hospital Universitario Marqués de Valdecilla, Santander, Spain
| | - Maria Alsina
- Medical Oncology Department, Complejo Hospitalario de Navarra, Pamplona Vall Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Ana Custodio
- Medical Oncology Department, Hospital Universitario La Paz, CIBERONC CB16/12/00398, Madrid, Spain
| | - Olbia Serra
- Medical Oncology Department, Catalan Institute of Oncology, L’Hospitalet, Spain
| | - Diego Cacho Lavin
- Medical Oncology Department, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain
| | - María Luisa Limón
- Medical Oncology Department, Hospital Universitario Virgen del Rocío, Sevilla, Spain
| | - Tamara Sauri
- Medical Oncology Department, Hospital Clinic, IDIBAPS, Barcelona, Spain
| | - Flora López
- Medical Oncology Department, Hospital Universitario Doce de Octubre, Madrid, Spain
| | - Laura Visa
- Medical Oncology Department, Hospital Universitario El Mar, Barcelona, Spain
| | - Mónica Granja
- Medical Oncology Department, Hospital Universitario Clínico San Carlos, Madrid, Spain
| | - Nieves Martínez Lago
- Medical Oncology Department, Complejo Hospitalario Universitario de A Coruña, A Coruña, Spain
| | - Virginia Arrazubi
- Medical Oncology Department, Complejo Hospitalario de Navarra, IdiSNA (Navarra Institute for Health Research), Pamplona, Spain
| | - Rosario Vidal Tocino
- Medical Oncology Department, Complejo Asistencial Universitario de Salamanca-IBSAL, Salamanca, Spain
| | - Raquel Hernandez
- Medical Oncology Department, Hospital Universitario de Canarias, Tenerife, Spain
| | - Gema Aguado
- Medical Oncology Department, Hospital Universitario Gregorio Marañón, Madrid, Spain
| | - Juana María Cano
- Medical Oncology Department, Hospital General Universitario de Ciudad Real, Ciudad Real, Spain
| | | | - Monserrat Mangas
- Medical Oncology Department, Hospital Galdakao-Usansolo, Usansolo, Spain
| | - Paola Pimentel
- Medical Oncology Department, Hospital General Universitario Santa Lucía, Cartagena, Spain
| | | | | | - Federico Longo
- Medical Oncology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - Avinash Ramchandani
- Medical Oncology Department, Hospital Universitario Insular de Gran Canaria, Las Palmas de Gran Canaria, Spain
| | - Marta Martín Richard
- Medical Oncology Department, Hospital Universitario Santa Creu i Sant Pau, Barcelona, Spain
| | - Alicia Hurtado
- Medical Oncology Department, Hospital Universitario Fundación Alcorcón, Madrid, Spain
| | - Aitor Azkarate
- Medical Oncology Department, Hospital Universitario Son Espases, Mallorca, Spain
| | - Carolina Hernández Pérez
- Medical Oncology Department, Hospital Universitario Nuestra Señora de the Candelaria, Tenerife, Spain
| | - Raquel Serrano
- Medical Oncology Department, Hospital Universitario Reina Sofía, Córdoba, Spain
| | - Javier Gallego
- Medical Oncology Department, Hospital General Universitario of Elche, Elche, Spain
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Prevalence of HER2 overexpression and amplification in squamous cell carcinoma of the esophagus: A systematic review and meta-analysis. Crit Rev Oncol Hematol 2021; 161:103339. [PMID: 33865993 DOI: 10.1016/j.critrevonc.2021.103339] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 03/26/2021] [Accepted: 03/26/2021] [Indexed: 11/22/2022] Open
Abstract
Accurate data on HER2 positivity in esophageal squamous cell carcinoma patients (ESCC) is lacking. We conducted a systematic review and meta-analysis (Single Incidence Rates; metarate package, R) to examine the prevalence of HER2 in ESCC. Data on in situ hybridization (ISH) and immunohistochemistry (IHC) were extracted to derive pooled prevalence estimates, characteristics of the studies were extracted for subgroup analysis. Eighteen studies with 1505 patients were identified. HER2 gene amplification by ISH were prevalent in 10 % (95 % CI 6.9 %-15 %). Prevalence of HER2 overexpression (IHC3+) and borderline HER2 expression (IHC2+) were 6 % (95 % CI: 3.5 %-8.7 %) and 10 % (95 % CI: 6.0 %-17 %), respectively. An estimated 8.6 % (95 % CI: 5.5 %-13 %) of ESCC were HER2 positive using initial IHC followed by reflex ISH confirmation of borderline HER2 expression. In conclusion: Estimated prevalence of HER 2 positivity in ESCC were 10 % assessed by ISH and 8.6 % assessed by initial IHC followed by ISH.
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18
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Secretory Phospholipase A2 IIa Mediates Expression of Growth Factor Receptors in Esophageal Adenocarcinoma. Dig Dis Sci 2021; 66:784-795. [PMID: 32277371 DOI: 10.1007/s10620-020-06241-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Accepted: 03/26/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Receptor tyrosine kinases of the epidermal growth factor receptor (EGFR) family such as human epidermal receptor-2 (HER2) are involved in the development and progression of esophageal adenocarcinoma (EAC). Prior studies have demonstrated that group IIa secretory phospholipase A2 (sPLA2 IIa) can function as a ligand for the EGFR family of receptors and lead to an increase in receptor signaling. AIMS We hypothesized that sPLA2 IIa inhibition downregulates the expression of EGFR and HER-2 in EAC and through this mechanism decreases proliferation in EAC. METHODS Normal human esophageal epithelium, Barrett's esophagus (BE), and EAC tissue samples were assayed for baseline expression of EGFR, HER-2, and sPLA2 IIa. sPLA2 IIa was attenuated via inhibitor or lentiviral knockdown in esophageal cell lines, and cells were assayed for EGFR and HER2 expression as well as proliferation. FLO1 EAC cells were injected into the flank of nude mice. After randomization, mice received daily group IIA sPLA2 inhibitor or a control solution, and tumor volume was measured with calipers. RESULTS sPLA2 IIa, EGFR, and HER2 expression increased across the spectrum of normal esophageal epithelium to EAC. sPLA2 IIa inhibition and knockdown decreased the expression of HER-2 and EGFR and proliferation. Mice treated with sPLA2 IIa inhibitor had smaller tumors than controls. CONCLUSIONS sPLA2 IIa inhibition decreases EGFR and HER2 expression and lowers proliferation of human EAC. The discovery of sPLA2 IIa inhibition's ability to attenuate growth factor receptor signaling underscores the exciting potential of sPLA2 IIa inhibitors as therapeutics in the treatment of EAC.
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19
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Gotovac JR, Liu DSH, Yates MJ, Milne JV, Macpherson AA, Simpson KJ, Eslick GD, Mitchell C, Duong CP, Phillips WA, Clemons NJ. GRB7 is an oncogenic driver and potential therapeutic target in oesophageal adenocarcinoma. J Pathol 2020; 252:317-329. [PMID: 32737994 PMCID: PMC7693356 DOI: 10.1002/path.5528] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Revised: 07/12/2020] [Accepted: 07/26/2020] [Indexed: 12/27/2022]
Abstract
Efficacious therapeutic approaches are urgently needed to improve outcomes in patients with oesophageal adenocarcinoma (OAC). However, oncogenic drivers amenable to targeted therapy are limited and their functional characterisation is essential. Among few targeted therapies available, anti-human epidermal growth factor receptor 2 (HER2) therapy showed only modest benefit for patients with OAC. Herein, we investigated the potential oncogenic role of growth factor receptor bound protein 7 (GRB7), which is reported to be co-amplified with HER2 (ERBB2) in OAC. GRB7 was highly expressed in 15% of OAC tumours, not all of which could be explained by co-amplification with HER2, and was associated with a trend for poorer overall survival. Knockdown of GRB7 decreased proliferation and clonogenic survival, and induced apoptosis. Reverse phase protein array (RPPA) analyses revealed a role for PI3K, mammalian target of rapamycin (mTOR), MAPK, and receptor tyrosine kinase signalling in the oncogenic action of GRB7. Furthermore, the GRB7 and HER2 high-expressing OAC cell line Eso26 showed reduced cell proliferation upon GRB7 knockdown but was insensitive to HER2 inhibition by trastuzumab. Consistent with this, GRB7 knockdown in vivo with an inducible shRNA significantly inhibited tumour growth in cell line xenografts. HER2 expression did not predict sensitivity to trastuzumab, with Eso26 xenografts remaining refractory to trastuzumab treatment. Taken together, our study provides strong evidence for an oncogenic role for GRB7 in OAC and suggests that targeting GRB7 may be a potential therapeutic strategy for this cancer. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Jovana R Gotovac
- Division of Cancer ResearchPeter MacCallum Cancer CentreMelbourneVictoriaAustralia
- Sir Peter MacCallum Department of OncologyThe University of MelbourneParkvilleVictoriaAustralia
| | - David SH Liu
- Division of Cancer ResearchPeter MacCallum Cancer CentreMelbourneVictoriaAustralia
- Sir Peter MacCallum Department of OncologyThe University of MelbourneParkvilleVictoriaAustralia
| | - Michael J Yates
- Division of Cancer ResearchPeter MacCallum Cancer CentreMelbourneVictoriaAustralia
| | - Julia V Milne
- Division of Cancer ResearchPeter MacCallum Cancer CentreMelbourneVictoriaAustralia
- Sir Peter MacCallum Department of OncologyThe University of MelbourneParkvilleVictoriaAustralia
| | - Arthi A Macpherson
- Division of Cancer ResearchPeter MacCallum Cancer CentreMelbourneVictoriaAustralia
| | - Kaylene J Simpson
- Division of Cancer ResearchPeter MacCallum Cancer CentreMelbourneVictoriaAustralia
- Sir Peter MacCallum Department of OncologyThe University of MelbourneParkvilleVictoriaAustralia
| | - Guy D Eslick
- Nepean Clinical SchoolThe University of SydneyKingswoodNew South WalesAustralia
| | - Catherine Mitchell
- Division of Cancer ResearchPeter MacCallum Cancer CentreMelbourneVictoriaAustralia
- Department of PathologyPeter MacCallum Cancer CentreMelbourneVictoriaAustralia
| | - Cuong P Duong
- Division of Cancer ResearchPeter MacCallum Cancer CentreMelbourneVictoriaAustralia
- Sir Peter MacCallum Department of OncologyThe University of MelbourneParkvilleVictoriaAustralia
| | - Wayne A Phillips
- Division of Cancer ResearchPeter MacCallum Cancer CentreMelbourneVictoriaAustralia
- Sir Peter MacCallum Department of OncologyThe University of MelbourneParkvilleVictoriaAustralia
- Department of Surgery (St Vincent's Hospital)The University of MelbourneParkvilleVictoriaAustralia
| | - Nicholas J Clemons
- Division of Cancer ResearchPeter MacCallum Cancer CentreMelbourneVictoriaAustralia
- Sir Peter MacCallum Department of OncologyThe University of MelbourneParkvilleVictoriaAustralia
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20
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Abdelhakeem A, Wang X, Rogers JE, Trail A, Zhao M, Blum-Murphy M, Estrella JS, Ajani JA. Outcomes of Advanced Gastroesophageal Cancer Patients with Equivocal HER2 Expression with or without ERBB2 Gene Amplification. Oncology 2020; 98:884-888. [PMID: 32998149 PMCID: PMC10604547 DOI: 10.1159/000509148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 06/02/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND Prior studies have shown that patients whose tumor overexpresses Her2 at 3+ level by immunohistochemistry (IHC) fare better than those whose tumor overexpresses Her2 at 2+ level (with ERBB2 amplified). Therefore, it would be important to compare the outcome of patients whose tumor expresses Her2 at 2+ level but further classify by gene amplification studies as positive or negative. METHODS We retrospectively identified patients with advanced gastroesophageal adenocarcinoma with low Her2 protein expression (2+ by IHC) whose tumors were evaluated for gene amplification of ERBB2 by fluorescence in situ hybridization (FISH). All patients received first-line therapy, and trastuzu-mab was added according to Her2 status. We compared overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) of the entire cohort and compared Her2-positive tumor patients' outcomes with Her2-negative tumor patients' outcomes. All patients had treatment response assessments and follow-ups at our institution. RESULTS We identified 87 patients whose tumors expressed Her2 at 2+ level. 51 (58.6%) were Her2-negative and 36 (41.4%) were Her2-positive by FISH. For the entire cohort, the median OS was 26 months (95% confidence interval 16.6-37.6), and the median PFS was 12.2 months (95% confidence interval 9.7-19.3). Median OS, median PFS, and ORR did not differ between Her2-positive and Her2-negative patients (p = 0.70, p = 0.60, p = 0.91, respectively). CONCLUSIONS Our data suggest that patients with Her2 positivity or negativity when tumors have lower Her2 protein expression (2 + by IHC) have similar clinical outcomes. Further research is warranted in this cohort.
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Affiliation(s)
- Ahmed Abdelhakeem
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Xuemei Wang
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jane E Rogers
- Pharmacy Clinical Programs, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Allison Trail
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Meina Zhao
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Mariela Blum-Murphy
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - J S Estrella
- Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA,
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21
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Muhetaer A, Niyaz M, Ainiwaer J, Liwei Z, Awut E. Amplification and clinicopathological significance of HER-2 in Kazakh esophageal squamous cell carcinoma. Mol Clin Oncol 2020; 13:64. [PMID: 32968485 PMCID: PMC7500049 DOI: 10.3892/mco.2020.2134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 08/25/2020] [Indexed: 11/06/2022] Open
Abstract
Amplification and overexpression of the human epidermal growth factor receptor-2 (HER-2) gene accelerates cell division and proliferation, and promotes tumor growth and metastasis in various malignant tumors. However, there are few reports on its influence and mechanism in esophageal cancer. The aim of the present study was to investigate the gene amplification and clinicopathological significance of HER-2 in Kazakh esophageal squamous cell carcinoma (ESCC). HER-2 gene amplification was detected in 70 esophageal cancer tissues using fluorescence in situ hybridization. The association between the HER-2 gene amplification and the clinicopathological characteristics of patients with esophageal cancer was also analyzed. The amplification rate of the HER-2 gene in patients with esophageal cancer was 54.2% (38/70). The results also revealed a positive association between the amplification rate of the HER-2 gene in esophageal squamous cell carcinomas and the level of tissue differentiation, increasing gradually and significantly among the highly, moderately and poorly differentiated tissues (P<0.05). The amplification rate of the HER-2 gene in patients with lymph node metastasis was higher than those without (P<0.05). There was no significant association between the amplification rate of the HER-2 gene and any of the clinic pathological parameters, such as sex, age, depth of invasion and 3-year survival, among patients (P>0.05). In conclusion, the amplification rate of the HER-2 gene in patients with Kazakh ESCC was high. There was an association with various prognostic factors, including cancer differentiation and lymph node metastasis. HER-2 gene expression levels may be considered as an indicator of poor prognosis in patients with ESCC in the clinical setting, and this may provide a basis of treatment for individualized targeted therapies.
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Affiliation(s)
- Aishanjiang Muhetaer
- Department of Thoracic Surgery, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China.,Department of Thoracic Surgery, Kashi First People's Hospital, Kashi, Xinjiang 844000, P.R. China
| | - Madiniyet Niyaz
- First Affiliated Hospital/Clinical Medicine Research Institute of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Julaiti Ainiwaer
- Department of Thoracic Surgery, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Zhang Liwei
- Department of Thoracic Surgery, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Edris Awut
- Department of Thoracic Surgery, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
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22
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Abstract
Management of locally advanced esophageal cancer is evolving. Trimodality therapy with chemoradiation followed by surgical resection has become the standard of care. However, the value of planned surgery after response to therapy is in question. In this article, we discuss the current practice principles and evidence for the treatment of locally advanced esophageal cancer. Topics will include various neoadjuvant therapies, trimodality versus bimodality therapy, and outcomes for salvage esophagectomies. In addition, emerging novel therapies, such as HER2 inhibitors and immunotherapy, are available for unresectable or metastatic disease, enabling a greater armamentarium of tumor biology-specific treatments.
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23
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Heidarpour M, Taheri M, Akhavan A, Goli P, Kefayat A. Investigation of HER-2 Expression an Its Correlation with Clinicopathological Parameters and Overall Survival of Esophageal Squamous Cell Carcinoma Patients. IRANIAN JOURNAL OF PATHOLOGY 2020; 15:274-281. [PMID: 32944039 PMCID: PMC7477677 DOI: 10.30699/ijp.2020.113829.2235] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 04/22/2020] [Indexed: 12/18/2022]
Abstract
Background & Objective: Human epidermal growth factor receptor 2 (HER-2) exhibits a vast range of expression in esophageal squamous cell carcinoma (ESCC) patients as a biomarker. This paper aimed to investigate HER-2 expression and clinicopathological parameters of esophageal SCC. Methods: HER-2 expression was assessed in 102 ESCC patients by immunohistochemistry. The HER-2 staining intensity , according to the Gastric HER2 Biomarker1.0.0.1 version of the college of American pathologists (CAP) protocol for gastric and gastroesophageal junction cancers, was graded as 0 (no reactivity in any of the cancer cells’ membranes); 1+ (pale or hardly noticeable reactivity in the membrane of cancer cells’ cluster [≥ 5 neoplastic cells] regardless of the positive cancer cells’ percentage); 2+ (weak-to-moderate complete, basolateral, or lateral membranous reactivity regardless of the positive cancer cells’ percentage); and 3+ ( strong complete, basolateral, or lateral reactivity in the membrane of the cancer cell cluster regardless of the positive cancer cells’ percentage).In this regard, 3+ scored samples were considered as positive. If HER-2 expression was scored 2+, an additional fluorescence in situ hybridization (FISH) was performed. Fisher's exact test was employed for investigating the correlation of HER-2 expression status with patients’ clinicopathological characteristics (including age, gender, tumor location, stage, grade, infiltration level, venous invasion, lymphatic invasion, and tumor recurrence). Kaplan-Meier analysis was done for the patients’ survival assessments. Results: Five patients (~5%) were HER-2 positive and no significant association was observed between HER-2 expression and clinicopathological properties. In addition, HER-2 expression status exhibited no significant association with the patients’ overall survival (P=0.9299). Conclusion: HER-2 is not a suitable prognostic biomarker for Iranian ESCC patients.
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Affiliation(s)
- Mitra Heidarpour
- Department of Pathology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mehran Taheri
- Department of Pathology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ali Akhavan
- Department of Radiation Oncology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Parvin Goli
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Amirhosein Kefayat
- Department of Oncology, Cancer Prevention Research Center, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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24
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Triggered Immune Response Induced by Antigenic Epitopes Covalently Linked with Immunoadjuvant-Pulsed Dendritic Cells as a Promising Cancer Vaccine. J Immunol Res 2020; 2020:3965061. [PMID: 32322595 PMCID: PMC7160722 DOI: 10.1155/2020/3965061] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 03/03/2020] [Accepted: 03/11/2020] [Indexed: 12/19/2022] Open
Abstract
The success of peptide-based dendritic cell (DC) cancer vaccines mainly depends on the utilized peptides and selection of an appropriate adjuvant. Herein, we aimed to evoke a broad immune response against multiple epitopes concurrently in the presence of immunoadjuvant. Three synthetic HLA-A∗0201-restricted peptides were separately linked with HMGB1-derived peptide (SAFFLFCSE, denoted as HB100-108) as immunoadjuvant via double arginine (RR) linker and loaded onto human monocyte-derived DCs. Peptide uptake was detected by immunofluorescence microscopy and flow cytometry. The maturation and activation status of pulsed DCs were monitored by detection of the expression of specific markers and released cytokines. The ability of peptide-pulsed DCs to activate allogeneic T cells has been assessed by a degranulation assay and detection of secreted cytokines. The lytic activity of effector T cells against cancer cells in vitro was analyzed by a lactate dehydrogenase (LDH) assay. Results revealed that DCs efficiently take up peptides+HB100-108 and expressed higher levels of surface markers (HLA-ABC, HLA-DR, CD80, CD86, CD83, CD40, and CCR7) and proinflammatory cytokines (IL-6, IFN-γ, TNF-α, and IL-12) than control DCs, free peptide-pulsed DCs, and free HB100-108-pulsed DC groups. Moreover, peptides+HB100-108/pulsed DCs were capable of activating allogeneic T cells and enhance their lytic activity against a pancreatic cancer cell line (PANC-1) in vitro. These findings suggest that antigenic peptides covalently linked with HB100-108/pulsed DCs could be a promising strategy to improve the current DC-based cancer vaccines.
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25
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Zhou N, Hofstetter WL. Prognostic and therapeutic molecular markers in the clinical management of esophageal cancer. Expert Rev Mol Diagn 2020; 20:401-411. [PMID: 32067548 DOI: 10.1080/14737159.2020.1731307] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Introduction: Esophageal cancer is a deadly disease with high mortality. Treatment with chemotherapy, radiation, and surgery continues to leave many patients with disease progression and recurrence. Novel treatments are needed for this patient population. The development of molecular markers are important for identifying therapeutic targets, as well as prognosis.Areas covered: This review evaluates three molecular markers in esophageal cancer: HER2, PD-L1, and MSI. The fundamentals of these markers, diagnosis, and rates of occurrence in esophageal cancer are explored. The prognostic potential of these markers is based on existing literature as well as application in clinical trials. Key trial findings pertaining to the therapeutic targets for HER2 and PD-1 as well as the role of MSI are discussed.Expert commentary: Molecular markers are changing the practice for esophageal cancer. Therapeutic targeting for HER2 and PD-L1 have shown positive results in recent clinical trials. Trials evaluating immunotherapy as first-line agents are currently underway.
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Affiliation(s)
- Nicolas Zhou
- Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Wayne L Hofstetter
- Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA
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26
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Stroes CI, Schokker S, Creemers A, Molenaar RJ, Hulshof MC, van der Woude SO, Bennink RJ, Mathôt RA, Krishnadath KK, Punt CJ, Verhoeven RH, van Oijen MG, Creemers GJ, Nieuwenhuijzen GA, van der Sangen MJ, Beerepoot LV, Heisterkamp J, Los M, Slingerland M, Cats A, Hospers GA, Bijlsma MF, van Berge Henegouwen MI, Meijer SL, van Laarhoven HW. Phase II Feasibility and Biomarker Study of Neoadjuvant Trastuzumab and Pertuzumab With Chemoradiotherapy for Resectable Human Epidermal Growth Factor Receptor 2-Positive Esophageal Adenocarcinoma: TRAP Study. J Clin Oncol 2020; 38:462-471. [PMID: 31809243 PMCID: PMC7007286 DOI: 10.1200/jco.19.01814] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/08/2019] [Indexed: 12/24/2022] Open
Abstract
PURPOSE Approximately 15% to 43% of esophageal adenocarcinomas (EACs) are human epidermal growth factor receptor 2 (HER2) positive. Because dual-agent HER2 blockade demonstrated a survival benefit in breast cancer, we conducted a phase II feasibility study of trastuzumab and pertuzumab added to neoadjuvant chemoradiotherapy (nCRT) in patients with EAC. PATIENTS AND METHODS Patients with resectable HER2-positive EAC received standard nCRT with carboplatin and paclitaxel and 41.4 Gy of radiotherapy, with 4 mg/kg of trastuzumab on day 1, 2 mg/kg per week during weeks 2 to 6, and 6 mg/kg per week during weeks 7, 10, and 13 and 840 mg of pertuzumab every 3 weeks. The primary end point was feasibility, defined as ≥ 80% completion of treatment with both trastuzumab and pertuzumab. An exploratory comparison of survival with a propensity score-matched cohort receiving standard nCRT was performed, as were exploratory pharmacokinetic and biomarker analyses. RESULTS Of the 40 enrolled patients (78% men; median age, 63 years), 33 (83%) completed treatment with trastuzumab and pertuzumab. No unexpected safety events were observed. R0 resection was achieved in all patients undergoing surgery, with pathologic complete response in 13 patients (34%). Three-year progression-free and overall survival (OS) were 57% and 71%, respectively (median follow-up, 32.1 months). Compared with the propensity score-matched cohort, a significantly longer OS was observed with HER2 blockade (hazard ratio, 0.58; 95% CI, 0.34 to 0.97). Results of pharmacokinetic analysis and activity on [18F]fluorodeoxyglucose positron emission tomography scans did not correlate with survival or pathologic response. Patients with HER2 3+ overexpression or growth factor receptor-bound protein 7 (Grb7) -positive tumors at baseline demonstrated significantly better survival (P = .007) or treatment response (P = .016), respectively. CONCLUSION Addition of trastuzumab and pertuzumab to nCRT in patients with HER2-positive EAC is feasible and demonstrates potentially promising activity compared with historical controls. HER2 3+ overexpression and Grb7 positivity are potentially predictive for survival and treatment response, respectively.
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Affiliation(s)
- Charlotte I. Stroes
- Amsterdam University Medical Center, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Sandor Schokker
- Amsterdam University Medical Center, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Aafke Creemers
- Amsterdam University Medical Center, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Remco J. Molenaar
- Amsterdam University Medical Center, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Maarten C.C.M. Hulshof
- Amsterdam University Medical Center, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Stephanie O. van der Woude
- Amsterdam University Medical Center, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Roel J. Bennink
- Amsterdam University Medical Center, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Ron A.A. Mathôt
- Amsterdam University Medical Center, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Kausilia K. Krishnadath
- Amsterdam University Medical Center, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Cornelis J.A. Punt
- Amsterdam University Medical Center, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | | | - Martijn G.H. van Oijen
- Amsterdam University Medical Center, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | | | | | | | | | | | - Maartje Los
- Sint Antonius Hospital, Nieuwegein, the Netherlands
| | | | - Annemieke Cats
- Netherlands Cancer Institute, Amsterdam, the Netherlands
| | | | - Maarten F. Bijlsma
- Amsterdam University Medical Center, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands
- Oncode Institute, Amsterdam, the Netherlands
| | - Mark I. van Berge Henegouwen
- Amsterdam University Medical Center, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Sybren L. Meijer
- Amsterdam University Medical Center, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Hanneke W.M. van Laarhoven
- Amsterdam University Medical Center, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands
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27
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Abd El-kader AM, Mahmoud BK, Hajjar D, Mohamed MFA, Hayallah AM, Abdelmohsen UR. Antiproliferative activity of new pentacyclic triterpene and a saponin from Gladiolus segetum Ker-Gawl corms supported by molecular docking study. RSC Adv 2020; 10:22730-22741. [PMID: 35514559 PMCID: PMC9054649 DOI: 10.1039/d0ra02775h] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 05/25/2020] [Indexed: 11/23/2022] Open
Abstract
A new triterpenoidal saponin identified as 3-O-[β-d-glucopyranosyl-(1 → 2)-β-d-glucopyranosyl-(1 → 4)-β-d-xylopyranosyl]-2β,3β,16α-trihydroxyolean-12-en-23,28-dioic acid-28-O-α-l-rhamnopyranosyl-(1 → 4)-α-l-rhamnopyranosyl-(1 → 2)-β-d-glucopyranosyl-(1 → 2)-α-l-arabinopyranoside 1 together with a new oleanane triterpene identified as 2β,3β,13α,22α-tetrahydroxy olean-23,28-dioic acid 2 and 6 known compounds (3–8) have been isolated from Gladiolus segetum Ker-Gawl corms. The structural elucidation of the isolated compounds was confirmed using different chemical and spectroscopic methods, including 1D and 2D NMR experiments as well as HR-ESI-MS. Moreover, the in vitro cytotoxic activity of the fractions and that of the isolated compounds 1–8 were investigated against five human cancer cell lines (PC-3, A-549, HePG-2, MCF-7 and HCT-116) using doxorubicin as a reference drug. The results showed that the saponin fraction exhibited potent in vitro cytotoxic activity against the five human cancer cell lines, whereas the maximum activity was exhibited against the PC-3 and A-549 cell lines with the IC50 values of 1.13 and 1.98 μg mL−1, respectively. In addition, compound 1 exhibited potent activity against A-549 and PC-3 with the IC50 values of 2.41 μg mL−1 and 3.45 μg mL−1, respectively. Interestingly, compound 2 showed the maximum activity against PC-3 with an IC50 of 2.01 μg mL−1. These biological results were in harmony with that of the molecular modeling study, which showed that the cytotoxic activity of compound 2 might occur through the inhibition of the HER-2 enzyme. A new triterpenoidal saponin 1, a new oleanane triterpene 2, and 6 known compounds (3–8) have been isolated from Gladiolus segetum Ker-Gawl corms.![]()
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Affiliation(s)
| | | | - Dina Hajjar
- Department of Biochemistry
- Collage of Science
- University of Jeddah
- 80203 Jeddah
- Saudi Arabia
| | - Mamdouh F. A. Mohamed
- Department of Pharmaceutical Chemistry
- Faculty of Pharmacy
- Sohag University
- 82524 Sohag
- Egypt
| | - Alaa M. Hayallah
- Pharmaceutical Chemistry Department
- Faculty of Pharmacy
- Deraya University
- Minia
- Egypt
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28
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Wachowiak R, Mayer S, Suttkus A, Martynov I, Lacher M, Melling N, Izbicki JR, Tachezy M. CHL1 and NrCAM are Primarily Expressed in Low Grade Pediatric Neuroblastoma. Open Med (Wars) 2019; 14:920-927. [PMID: 31989042 PMCID: PMC6972343 DOI: 10.1515/med-2019-0109] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 10/19/2019] [Indexed: 12/28/2022] Open
Abstract
Background Neural cell adhesion molecules like close homolog of L1 protein (CHL1) and neuronal glia related cell adhesion molecule (NrCAM) play an important role in development and regeneration of the central nervous system. However, they are also associated with cancerogenesis and progression in adult malignancies, thus gain increasing importance in cancer research. We therefore studied the expression of CHL1 and NrCAM according to the course of disease in children with neuroblastoma. Methods CHL1 and NrCAM expression levels were histologically assessed by tissue microarrays from surgically resected neuroblastoma specimens of 56 children. Expression of both markers was correlated to demographics as well as clinical data including metastatic dissemination and survival. Results CHL1 was expressed in 9% and NrCAM in 51% of neuroblastoma tissue samples. Expression of CHL1 was higher in patients with low Hughes grade 1a/b (p=0.01). NrCAM was more often detected in patients with a low International Staging System (INSS) score 1/2 (p=0.04). Conclusion CHL1 and NrCAM expression was associated with low-grade pediatric neuroblastoma. These adhesion molecules may play a role in early tumor development of neuroblastoma.
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Affiliation(s)
- Robin Wachowiak
- Department of Pediatric Surgery, University Hospital Leipzig, Liebigstrasse 20 A, 04103 Leipzig, Germany
| | - Steffi Mayer
- Department of Pediatric Surgery, University Hospital Leipzig, Liebigstrasse 20 A, 04103 Leipzig, Germany
| | - Anne Suttkus
- Department of Pediatric Surgery, University Hospital Leipzig, Liebigstrasse 20 A, 04103 Leipzig, Germany
| | - Illya Martynov
- Department of Pediatric Surgery, University Hospital Leipzig, Liebigstrasse 20 A, 04103 Leipzig, Germany
| | - Martin Lacher
- Department of Pediatric Surgery, University Hospital Leipzig, Liebigstrasse 20 A, 04103 Leipzig, Germany
| | - Nathaniel Melling
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg Eppendorf, Hamburg, 20246, Germany
| | - Jakob R Izbicki
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg Eppendorf, Hamburg, 20246, Germany
| | - Michael Tachezy
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg Eppendorf, Hamburg, 20246, Germany
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29
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Parakh S, King D, Gan HK, Scott AM. Current Development of Monoclonal Antibodies in Cancer Therapy. Recent Results Cancer Res 2019; 214:1-70. [PMID: 31473848 DOI: 10.1007/978-3-030-23765-3_1] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Exploiting the unique specificity of monoclonal antibodies has revolutionized the treatment and diagnosis of haematological and solid organ malignancies; bringing benefit to millions of patients over the past decades. Recent achievements include conjugating antibodies with toxic payloads resulting in superior efficacy and/or reduced toxicity, development of molecular imaging techniques targeting specific antigens for use as predictive and prognostic biomarkers, the development of novel bi- and tri-specific antibodies to enhance therapeutic benefit and abrogate resistance and the success of immunotherapy agents. In this chapter, we review an overview of antibody structure and function relevant to cancer therapy and provide an overview of pivotal clinical trials which have led to regulatory approval of monoclonal antibodies in cancer treatment. We further discuss resistance mechanisms and the unique side effects of each class of antibody and provide an overview of emerging therapeutic agents.
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Affiliation(s)
- Sagun Parakh
- Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, 145 Studley Road, Heidelberg, Melbourne, VIC, 3084, Australia.,Department of Medical Oncology, Olivia Newton-John Cancer and Wellness Centre, Austin Health, Heidelberg, Melbourne, Australia.,School of Cancer Medicine, La Trobe University, Melbourne, Australia
| | - Dylan King
- Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, 145 Studley Road, Heidelberg, Melbourne, VIC, 3084, Australia.,School of Cancer Medicine, La Trobe University, Melbourne, Australia
| | - Hui K Gan
- Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, 145 Studley Road, Heidelberg, Melbourne, VIC, 3084, Australia.,Department of Medical Oncology, Olivia Newton-John Cancer and Wellness Centre, Austin Health, Heidelberg, Melbourne, Australia.,School of Cancer Medicine, La Trobe University, Melbourne, Australia
| | - Andrew M Scott
- Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, 145 Studley Road, Heidelberg, Melbourne, VIC, 3084, Australia. .,School of Cancer Medicine, La Trobe University, Melbourne, Australia. .,Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia. .,Department of Medicine, University of Melbourne, Melbourne, Australia.
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30
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Caspa Gokulan R, Garcia-Buitrago MT, Zaika AI. From genetics to signaling pathways: molecular pathogenesis of esophageal adenocarcinoma. Biochim Biophys Acta Rev Cancer 2019; 1872:37-48. [PMID: 31152823 PMCID: PMC6692203 DOI: 10.1016/j.bbcan.2019.05.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 05/10/2019] [Accepted: 05/10/2019] [Indexed: 02/07/2023]
Abstract
Esophageal adenocarcinoma (EAC) has one of the fastest rising incidence rates in the U.S. and many other Western countries. One of the unique risk factors for EAC is gastroesophageal reflux disease (GERD), a chronic digestive condition in which acidic contents from the stomach, frequently mixed with duodenal bile, enter the esophagus resulting in esophageal tissue injury. At the cellular level, progression to EAC is underlined by continuous DNA damage caused by reflux and chronic inflammatory factors that increase the mutation rate and promote genomic instability. Despite recent successes in cancer diagnostics and treatment, EAC remains a poorly treatable disease. Recent research has shed new light on molecular alterations underlying progression to EAC and revealed novel treatment options. This review focuses on the genetic and molecular studies of EAC. The molecular changes that occur during the transformation of normal Barrett's esophagus to esophageal adenocarcinoma are also discussed.
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Affiliation(s)
| | | | - Alexander I Zaika
- Department of Surgery, University of Miami, Miami, FL, United States of America; Department of Veterans Affairs, Miami VA Healthcare System, Miami, FL, United States of America.
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31
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Ajani JA, D'Amico TA, Bentrem DJ, Chao J, Corvera C, Das P, Denlinger CS, Enzinger PC, Fanta P, Farjah F, Gerdes H, Gibson M, Glasgow RE, Hayman JA, Hochwald S, Hofstetter WL, Ilson DH, Jaroszewski D, Johung KL, Keswani RN, Kleinberg LR, Leong S, Ly QP, Matkowskyj KA, McNamara M, Mulcahy MF, Paluri RK, Park H, Perry KA, Pimiento J, Poultsides GA, Roses R, Strong VE, Wiesner G, Willett CG, Wright CD, McMillian NR, Pluchino LA. Esophageal and Esophagogastric Junction Cancers, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2019; 17:855-883. [PMID: 31319389 DOI: 10.6004/jnccn.2019.0033] [Citation(s) in RCA: 665] [Impact Index Per Article: 110.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Esophageal cancer is the sixth leading cause of cancer-related deaths worldwide. Squamous cell carcinoma is the most common histology in Eastern Europe and Asia, and adenocarcinoma is most common in North America and Western Europe. Surgery is a major component of treatment of locally advanced resectable esophageal and esophagogastric junction (EGJ) cancer, and randomized trials have shown that the addition of preoperative chemoradiation or perioperative chemotherapy to surgery significantly improves survival. Targeted therapies including trastuzumab, ramucirumab, and pembrolizumab have produced encouraging results in the treatment of patients with advanced or metastatic disease. Multidisciplinary team management is essential for all patients with esophageal and EGJ cancers. This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on recommendations for the management of locally advanced and metastatic adenocarcinoma of the esophagus and EGJ.
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Affiliation(s)
| | | | - David J Bentrem
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | | | - Prajnan Das
- The University of Texas MD Anderson Cancer Center
| | | | | | | | - Farhood Farjah
- Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance
| | | | | | | | | | | | | | | | | | | | - Rajesh N Keswani
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | | | | | | | - Michael McNamara
- Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | - Mary F Mulcahy
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | - Haeseong Park
- Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
| | - Kyle A Perry
- The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | | | | | - Robert Roses
- Abramson Cancer Center at the University of Pennsylvania
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Dai X, Zhang X, Yu J. Clinicopathological features and Borrmann classification associated with HER2-positive in primary gastric cancer. Clin Exp Gastroenterol 2019; 12:287-294. [PMID: 31303779 PMCID: PMC6605773 DOI: 10.2147/ceg.s212895] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Accepted: 05/27/2019] [Indexed: 12/19/2022] Open
Abstract
PURPOSE Human epidermal growth factor receptor 2 (HER2) assesment is important for patients with advanced gastric cancer (GC) to determine trastuzumab therapy is being considered. A study was performed to evaluate the rate of HER2 positivity in patients with primary gastric cancer and to assess the relationship between HER2-positive and Borrmann classification. PATIENTS AND METHODS Four hundred and sixty-one patients with gastric or gastroesophageal junction cancer were confirmed as having adenocarcinoma between 2005 and 2016. HER2 status was assessed using immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH). Tissues were considered to be HER2-positive when assessment revealed either an IHC score of 3+ or IHC score 2+ accompanied by a positive FISH result. RESULTS The HER2-positive rate was significantly higher in men than in women (19% vs 9%; p=0.006). In our study, HER2-positive gastric tumors with differentiated histology were significantly higher. The proportion of HER2-positive gastric tumors of Borrmann classification III or IV was significantly higher than tumors classified as I or II. CONCLUSIONS HER2-positive gastric cancer tends to be associated with male gender, differentiated histology, and Borrmann tumor classification of III or IV.
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Affiliation(s)
- Xiaomin Dai
- Department of Pathology, Zhejiang Hospital, Hangzhou, Zhejiang, People’s Republic of China
| | - Xijiong Zhang
- Department of Pathology, The No.1 People’s Hospital of Pinghu, Jiaxing, Zhejiang, People’s Republic of China
| | - Jin Yu
- Department of Pathology, Zhejiang Hospital, Hangzhou, Zhejiang, People’s Republic of China
- Department of Pathology, The No.1 People’s Hospital of Pinghu, Jiaxing, Zhejiang, People’s Republic of China
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Roy PS, Nyodu T, Hazarika M, Saikia BJ, Bhuyan C, Inamdar A, Nyuthe CW, Borthakur B, Sharma JD. Prevalence of HER2 Expression and Its Correlation with
Clinicopathological Parameters in Gastric or Gastroesophageal
Junction Adenocarcinoma in North-East Indian Population. Asian Pac J Cancer Prev 2019; 20:1139-1145. [PMID: 31030487 PMCID: PMC6948890 DOI: 10.31557/apjcp.2019.20.4.1139] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Objective: Human epidermal growth factor receptor 2 (erbb2/HER2) overexpression, has now been implicated in advanced gastric and gastroesophageal junction cancers. The study was conducted to determine the rate of HER2 positivity in patients with locally advanced or metastatic gastric and gastroesophageal adenocarcinoma in North-East India and to assess the impact of various demographic and clinical parameters on HER2 positivity. Methods: A total of 68 patients of age >18 years of gastric and gastroesophageal adenocarcinoma diagnosed on histopathological examination from September 2016 to February 2018 at Dr B Borooah Cancer Institute, Assam were enrolled for the observational (epidemiological) study. All patients were subjected to the HER2 immunohistochemistry test using a FDA-approved, standardized test kit. HER2 expression was correlated with various demographic and clinicopathological parameters. Results: The overall rate of HER2 positivity in the population studied was 56% (n=38). The rate was non-significantly higher in male, older age group (>60 years) and Hindu population. Similarly, HER2 positivity rate was higher in patients with well differentiated histology and was more common in patients with stage II and III diseases, but neither of the associations is statistically significant. HER2 positivity rate was significantly higher in proximal and in GEJ tumours (56% versus 44%, P=0.002). Conclusion: HER2 overexpression was evident in 56% of the North-East Indian patients with locally advanced and metastatic gastric and gastroesophageal adenocarcinoma. The overexpression correlated significantly with primary tumour site. Routine testing of gastric and gastroesophageal tumours for HER2 expression is recommended to provide a therapeutic advantage in Indian patients.
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Affiliation(s)
- Partha S Roy
- Department of Medical Oncology, Dr B Borooah Cancer Institute, Guwahati, Assam, India.
| | - Tomar Nyodu
- Department of Medical Oncology, Dr B Borooah Cancer Institute, Guwahati, Assam, India.
| | - Munlima Hazarika
- Department of Medical Oncology, Dr B Borooah Cancer Institute, Guwahati, Assam, India.
| | - B J Saikia
- Department of Medical Oncology, Dr B Borooah Cancer Institute, Guwahati, Assam, India.
| | - C Bhuyan
- Department of Medical Oncology, Dr B Borooah Cancer Institute, Guwahati, Assam, India.
| | - Amit Inamdar
- Department of Medical Oncology, Dr B Borooah Cancer Institute, Guwahati, Assam, India.
| | - C W Nyuthe
- Department of Medical Oncology, Dr B Borooah Cancer Institute, Guwahati, Assam, India.
| | - B Borthakur
- Department of Surgical Oncology, Dr B Borooah Cancer Institute, Guwahati, Assam, India
| | - J D Sharma
- Department of Pathology, Dr B Borooah Cancer Institute, Guwahati, Assam, India
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Huber AR, Buscaglia B, Koltz BR, Henry J, McMahon L, Guo J, Hicks DG, Whitney-Miller CL. Impact of Specimen Type and Specimen Number on HER2 Status in Gastroesophageal Junction and Gastric Adenocarcinoma. Am J Clin Pathol 2019; 151:461-468. [PMID: 30624589 DOI: 10.1093/ajcp/aqy166] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVES Human epidermal growth factor receptor 2 (HER2) is expressed in some gastric and gastroesophageal junction adenocarcinomas. There were two goals: assess the impact of specimen type on HER2 status and evaluate HER2 concordance with multiple specimens. METHODS All cases were evaluated by immunohistochemistry (IHC) for HER2 and interpreted using established criteria. Fluorescence in situ hybridization (FISH) was performed on a subset. RESULTS Of 460 specimens, 83.9% were IHC negative, 5.4% were equivocal, and 10.7% were IHC positive. Of those with FISH testing, 78.5% were FISH negative, and 21.5% were FISH positive. IHC-FISH concordance for biopsy specimens, resections, and metastases was 82%, 84%, and 86%, respectively. With one vs two vs three or more specimens, the HER2-positive rate increased from 10.5% to 18.1% to 24.1%, respectively. CONCLUSIONS HER2 testing may be performed on biopsy specimens with a relatively high concordance rate with resection specimens, and if multiple samples are analyzed from a single patient, the HER2-positive rate increases over twofold.
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Affiliation(s)
- Aaron R Huber
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
| | - Brandon Buscaglia
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
| | - Brooke R Koltz
- Department of Pathology, University of Toledo, Toledo, OH
| | - Jill Henry
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
| | - Loralee McMahon
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
| | - James Guo
- Northwestern University, Feinberg School of Medicine, Chicago, IL
| | - David G Hicks
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
| | - Christa L Whitney-Miller
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
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Plum PS, Gebauer F, Krämer M, Alakus H, Berlth F, Chon SH, Schiffmann L, Zander T, Büttner R, Hölscher AH, Bruns CJ, Quaas A, Loeser H. HER2/neu (ERBB2) expression and gene amplification correlates with better survival in esophageal adenocarcinoma. BMC Cancer 2019; 19:38. [PMID: 30621632 PMCID: PMC6325716 DOI: 10.1186/s12885-018-5242-4] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 12/21/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND HER2 (ERBB2 or HER2/neu) is a tyrosine-kinase increasing cell proliferation. Overexpression/amplification of HER2 is correlated with worse prognosis in solid malignancies. Consequently, HER2 targeting is established in breast and upper gastrointestinal tract cancer. There are conflicting data concerning the impact of HER2 overexpression on esophageal adenocarcinoma (EAC), as most studies do not differ between cancers of the esophagus/gastroesophageal junction and the stomach. The aim of this study was to analyze the expression/amplification of HER2 in EAC in correlation to clinicopathological data to verify its prognostic impact. METHODS We analyzed 428 EAC patients that underwent transthoracic thoraco-abdominal esophagectomy between 1997 and 2014. We performed HER2 immunohistochemistry (IHC) according to the guidelines and fluorescence-in-situ-hybridization (FISH) for IHC score2+, using tissue micro arrays (TMA) with up to eight biopsies from the surface and infiltration area of a single tumor for evaluating HER2-heterogeneity and single-spot TMA. The HER2-status was correlated with clinicopathological data. RESULTS HER2-positivity was found in up to 14.9% in our cohort (IHC score 3+ or IHC score 2+ with gene amplification) and demonstrated a significantly better overall survival (OS) in correlation to HER2-negative tumors (median OS 70.1 vs. 24.6 months, p = 0.006). HER2-overexpression was more frequently seen in lower tumor stages (pT1/pT2, p = 0.038), in the absence of lymphatic metastases (pN0/pN+, p = 0.020), and was significantly associated with better histological grading (G1/G2) (p = 0.041). CONCLUSION We demonstrated a positive prognostic impact of HER2 overexpression in a large cohort of EAC, contrary to other solid malignancies including gastric cancer and breast cancer, but consistent to the results of a large study on EAC from 2012.
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Affiliation(s)
- Patrick Sven Plum
- Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Cologne, Germany.,Gastrointestinal Cancer Group Cologne (GCGC), University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany
| | - Florian Gebauer
- Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Cologne, Germany.,Gastrointestinal Cancer Group Cologne (GCGC), University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany
| | - Max Krämer
- Institute of Pathology, University Hospital Cologne, Kerpener Str. 62, 50937, Cologne, Germany
| | - Hakan Alakus
- Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Cologne, Germany.,Gastrointestinal Cancer Group Cologne (GCGC), University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany
| | - Felix Berlth
- Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Cologne, Germany
| | - Seung-Hun Chon
- Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Cologne, Germany
| | - Lars Schiffmann
- Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Cologne, Germany
| | - Thomas Zander
- Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany.,Gastrointestinal Cancer Group Cologne (GCGC), University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany
| | - Reinhard Büttner
- Institute of Pathology, University Hospital Cologne, Kerpener Str. 62, 50937, Cologne, Germany
| | | | | | - Alexander Quaas
- Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Cologne, Germany.,Gastrointestinal Cancer Group Cologne (GCGC), University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany
| | - Heike Loeser
- Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Cologne, Germany. .,Gastrointestinal Cancer Group Cologne (GCGC), University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
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Ognjenovic L, Trajkovski G, Gjoshev S, Shumkovski A, Dzambaz D, Hadzi-Manchev D, Volcevski G, Fildishevski I, Nikolova D, Petrushevska G, Janevska V, Janevski V. HER2 Positive Gastric Carcinomas and Their Clinico-Pathological Characteristics. Open Access Maced J Med Sci 2018; 6:1187-1192. [PMID: 30087720 PMCID: PMC6062279 DOI: 10.3889/oamjms.2018.280] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 06/18/2018] [Accepted: 06/19/2018] [Indexed: 12/05/2022] Open
Abstract
BACKGROUND: HER2 protein expression in gastric carcinoma, in correlation with existing, acknowledged prognostic factors which include the parameters that determine the TNM stage of the disease, could become the basis for ongoing research in the field of molecular targeted and personalised therapy. AIM: To determine the expression of the HER2 protein in gastric carcinoma and to correlate the expression of a HER2 protein with clinicopathological characteristics of the disease. MATERIAL AND METHODS: The data of HER2 protein expression and the parameters of the TNM classification were obtained from the histopathological reports of the Institute of Pathology in Skopje, and for the clinical stage we used patient’s files from the University Clinic for Abdominal Surgery in Skopje. RESULTS: The analysis of the correlation of HER2 protein expression and TNM classification parameters pointed out a significant correlation between HER2 protein expression and intragastric localisation of gastric carcinoma (P = 0.005), and the tumour grade of differentiation (P = 0.034). There was also a positive correlation between HER2 protein expression pattern and positive lymph nodes in patients with gastric carcinoma (P = 0.03). The expression pattern of HER2 +++ was significantly more common registered in patients with positive lymph nodes (P = 0.03) CONCLUSION: The expression of HER2 protein could represent a biological marker with prognostic and predictive value in patients with gastric carcinoma. Considering the high mortality rate in patients with gastric carcinoma and lack of international standardised therapeutic approach, research of the role and significance of HER2 overexpression and Trastuzumab therapy may prove useful in the development of new therapeutic strategies.
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Affiliation(s)
- Ljubomir Ognjenovic
- University Clinic of Abdominal Surgery, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Gjorgji Trajkovski
- University Clinic of Abdominal Surgery, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Stojan Gjoshev
- University Clinic of Abdominal Surgery, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Aleksandar Shumkovski
- University Clinic of Abdominal Surgery, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Darko Dzambaz
- University Clinic of Abdominal Surgery, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Dragan Hadzi-Manchev
- University Clinic of Abdominal Surgery, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Goce Volcevski
- University Clinic of Abdominal Surgery, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Igor Fildishevski
- University Clinic for Surgery St. Naum Ohridski, Skopje, Republic of Macedonia
| | - Dafina Nikolova
- University Clinic of Gastroenterohepatology, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Gordana Petrushevska
- Institute of Pathology, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Vesna Janevska
- Institute of Pathology, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Vlado Janevski
- University Clinic of Abdominal Surgery, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
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Hoffmann M, Pasch S, Schamberger T, Maneck M, Möhlendick B, Schumacher S, Brockhoff G, Knoefel WT, Izbicki J, Polzer B, Stoecklein NH, Klein CA. Diagnostic pathology of early systemic cancer: ERBB2 gene amplification in single disseminated cancer cells determines patient survival in operable esophageal cancer. Int J Cancer 2017; 142:833-843. [PMID: 29044505 DOI: 10.1002/ijc.31108] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 09/07/2017] [Accepted: 09/28/2017] [Indexed: 11/05/2022]
Abstract
Early metastatic dissemination and evolution of disseminated cancer cells (DCCs) outside the primary tumor is one reason for the failure of adjuvant therapies because it generates molecular genotypes and phenotypes different from primary tumors, which still underlie therapy decisions. Since ERBB2 amplification in esophageal DCCs but not in primary tumor cells predict outcome, we aimed to establish an assay with diagnostic reliability for single DCCs or circulating tumor cells. For this, we evaluated copy number alterations of more than 600 single DCCs from multiple cancer types to define reference regions suitable for quantification of target regions, such as ERBB2. We then compared ERBB2 quantitative PCR (qPCR) measurements with fluorescent in situ hybridization (FISH) data of various breast cancer cell lines and identified the aberration-calling threshold. The method was applied to two independent cohorts of esophageal cancer patients from Hamburg (n = 59) and Düsseldorf (n = 53). We found a high correlation between the single cell qPCR assay and the standard FISH assay (R = 0.98) and significant associations between amplification and survival for both patient cohorts (Hamburg (HH), p = 0.033; Düsseldorf (D), p = 0.052; pooled HH + D, p = 0.002) when applied to DCCs of esophageal cancer patients. Detection of a single ERBB2-amplified DCC was the most important risk factor for death from esophageal cancer (relative risk = 4.22; 95% CI = 1.91-9.32; p < 0.001). In our study, we detected ERBB2-amplified cells in 7% of patients. These patients could benefit from anti-ERBB2 targeting therapies.
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Affiliation(s)
- Martin Hoffmann
- Division of Personalized Tumor Therapy, Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Regensburg, Germany
| | - Sophie Pasch
- Chair of Experimental Medicine and Therapy Research, University of Regensburg, Germany
| | - Thomas Schamberger
- Chair of Experimental Medicine and Therapy Research, University of Regensburg, Germany
| | - Matthias Maneck
- Chair of Experimental Medicine and Therapy Research, University of Regensburg, Germany
| | - Birte Möhlendick
- Department of General, Visceral and Pediatric Surgery, University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany
| | - Sarah Schumacher
- Department of General, Visceral and Pediatric Surgery, University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany
| | - Gero Brockhoff
- Department of Gynecology, Caritas-Hospital St. Josef, University of Regensburg, Germany
| | - Wolfram Trudo Knoefel
- Department of General, Visceral and Pediatric Surgery, University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany
| | - Jakob Izbicki
- Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Bernhard Polzer
- Division of Personalized Tumor Therapy, Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Regensburg, Germany
| | - Nikolas H Stoecklein
- Department of General, Visceral and Pediatric Surgery, University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany
| | - Christoph A Klein
- Division of Personalized Tumor Therapy, Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Regensburg, Germany.,Chair of Experimental Medicine and Therapy Research, University of Regensburg, Germany
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Song Q, Liu Y, Jiang D, Wang H, Huang J, Xu Y, Sujie A, Zeng H, Xu C, Hou Y. High amplification of FGFR1 gene is a delayed poor prognostic factor in early stage ESCC patients. Oncotarget 2017; 8:74539-74553. [PMID: 29088806 PMCID: PMC5650361 DOI: 10.18632/oncotarget.20215] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Accepted: 06/29/2017] [Indexed: 11/29/2022] Open
Abstract
Amplification of the fibroblast growth factor receptor 1 (FGFR1) is believed to predict response to FGFR inhibitors. The aim of this study was to investigate the frequency and the prognostic impact of FGFR1 amplification in patients with resected esophageal squamous cell carcinoma (ESCC) by using fluorescent in situ hybridization. Microarrayed paraffin embedded blocks were constructed, and the cohort of tissues came from 506 patients with ESCC. FGFR1 high amplification (FGFR1high) was defined by an FGFR1/centromere 8 ratio of ≥ 2.0, or average number of FGFR1 signals/tumor cell nucleus ≥ 6.0, or percentage of tumor cells containing ≥ 15 FGFR1 signals, or large cluster in ≥ 10% of cancer cells. FGFR1 low amplification was defined by ≥ 5 FGFR1 signals in ≥ 50% of cancer cells. Kaplan-Meier curves with log-rank tests and Cox proportional hazards model were used to analyze patients’ survival. Among 506 patients, high amplification, low amplification, and disomy were detected in 8.7%, 3.6% and 87.7%, respectively. In general, the FGFR1high group trended towards worse disease-free survival (DFS) and overall survival (OS) compared to the FGFR1 low amplification/disomy (FGFR1low/disomy) group (DFS, P=0.108; OS, P=0.112), but this trend was amplified for patients with DFS ≥ 30 months (DFS, P=0.009; OS, P=0.007). Furthermore, when patients were stratified into stage I-II and stage III-IV, the FGFR1high group directly presented with adverse DFS and OS than the FGFR1low/disomy group in stage I-II patients (DFS, P=0.019; OS, P=0.034), especially with DFS ≥ 30 months (DFS, P=0.002; OS, P=0.001). However, for patients in stage III-IV, FGFR1high had no effect on prognosis regardless of DFS time. FGFR1high occurs in a minority of ESCC, and it predicts delayed poor prognosis in stage I and II ESCC patients.
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Affiliation(s)
- Qi Song
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China
| | - Yalan Liu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China
| | - Dongxian Jiang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China
| | - Haixing Wang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China
| | - Jie Huang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China
| | - Yifan Xu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China
| | - Akesu Sujie
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China
| | - Haiying Zeng
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China
| | - Chen Xu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China
| | - Yingyong Hou
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China.,Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China
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39
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Evolution of anti-HER2 therapies for cancer treatment. Cancer Treat Rev 2017; 59:1-21. [PMID: 28715775 DOI: 10.1016/j.ctrv.2017.06.005] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Revised: 06/21/2017] [Accepted: 06/23/2017] [Indexed: 01/13/2023]
Abstract
The development of HER2-directed monoclonal antibodies and tyrosine kinase inhibitors have provided benefits to cancer patients, as well as produced many insights into the biology of the ErbB receptor family. Current therapies based on ErbB family members have resulted in improved overall survival with associated improvements in quality of life for the cancer patients that respond to treatment. Compared to monotherapy using either two antibodies to block the HER2 receptor blockade or combinatorial approaches with HER2 antibodies and standard therapies has provided additional benefits. Despite the therapeutic success of existing HER2 therapies, personalising treatment and overcoming resistance to these therapies remains a significant challenge. The heterogeneous intra-tumoural HER2 expression and lack of fully predictive and prognostic biomarkers remain significant barriers to improving the use of HER2 antibodies. Imaging modalities using radiolabelled pertuzumab and trastuzumab allow quantitative assessment of intra-tumoural HER2 expression, HER2 antibody saturation and the success of different drug delivery systems to be assessed. Molecular imaging with HER2 antibodies has the potential to be a non-invasive, predictive and prognostic technique capable of influencing therapeutic decisions, predicting response and failure of treatments as well as providing insights into receptor recycling and signalling. Similarly, conjugating HER2 antibodies with novel toxic payloads or combining HER2 antibodies with cellular immunotherapy provide exciting new opportunities for the management of tumours overexpressing HER2. Future research will lead to higher therapeutic responses, lower toxicities and providing insight into the mechanisms of resistance to HER2-targeted treatments.
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40
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Improving Pertuzumab production by gene optimization and proper signal peptide selection. Protein Expr Purif 2017; 135:24-32. [DOI: 10.1016/j.pep.2017.04.013] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2016] [Revised: 03/12/2017] [Accepted: 04/24/2017] [Indexed: 12/23/2022]
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Creemers A, Ter Veer E, de Waal L, Lodder P, Hooijer GKJ, van Grieken NCT, Bijlsma MF, Meijer SL, van Oijen MGH, van Laarhoven HWM. Discordance in HER2 Status in Gastro-esophageal Adenocarcinomas: A Systematic Review and Meta-analysis. Sci Rep 2017; 7:3135. [PMID: 28600510 PMCID: PMC5466678 DOI: 10.1038/s41598-017-03304-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 04/26/2017] [Indexed: 02/06/2023] Open
Abstract
Trastuzumab combined with chemotherapy is standard of care for HER2 positive advanced gastro-esophageal cancers. The reported prevalence of HER2 discordance between primary tumors and corresponding metastases varies, hampering uniform patient selection for HER2 targeted therapy. This meta-analysis explores the influence of HER2 assessment methods on this discordance and investigates the prevalence of HER2 discordance in gastro-esophageal adenocarcinomas. PubMed, Embase and Cochrane databases were searched until January 2016. Differences in discordance rate between strict and broad(er) definitions of HER2 status were assessed using random-effect pair-wise meta-analysis. Random-effect single-arm meta-analyses were performed to assess HER2 discordance and the prevalence of positive and negative conversion. A significantly lower discordance rate in HER2 status between primary tumors and corresponding metastases was observed using a strict vs. broad definition of HER2 status (RR = 0.58, 95%CI 0.41-0.82), with a pooled discordance rate of 6.2% and 12.2%, respectively. Using the strict definition of HER2 assessment pooled overall discordance was 7% (95%CI 5-10%). The lowest discordance rates between primary tumors and corresponding metastasis are observed when using a strict method of HER2 positivity. Treatment outcomes of different studies will be better comparable if selection of eligible patients for HER2 targeted therapy is based on this strict definition.
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Affiliation(s)
- A Creemers
- Cancer Center Amsterdam, Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
- Cancer Center Amsterdam, Department of Medical Oncology, AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
| | - E Ter Veer
- Cancer Center Amsterdam, Department of Medical Oncology, AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - L de Waal
- Cancer Center Amsterdam, Department of Medical Oncology, AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - P Lodder
- Department of Methodology and Statistics/Department of Medical and Clinical Psychology, Tilburg University, Warandelaan 2, 5037 AB, Tilburg, The Netherlands
| | - G K J Hooijer
- Department of Pathology, AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - N C T van Grieken
- Department of Pathology, VUMC, De Boelenlaan 1117, 1081 HV, Amsterdam, The Netherlands
| | - M F Bijlsma
- Cancer Center Amsterdam, Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - S L Meijer
- Department of Pathology, AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - M G H van Oijen
- Cancer Center Amsterdam, Department of Medical Oncology, AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - H W M van Laarhoven
- Cancer Center Amsterdam, Department of Medical Oncology, AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
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Samson P, Lockhart AC. Biologic therapy in esophageal and gastric malignancies: current therapies and future directions. J Gastrointest Oncol 2017; 8:418-429. [PMID: 28736629 PMCID: PMC5506284 DOI: 10.21037/jgo.2016.11.13] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Accepted: 09/27/2016] [Indexed: 12/14/2022] Open
Abstract
Biologic agents, including targeted antibodies as well as immunomodulators, are demonstrating unparalleled development and study across the entire spectrum of human malignancy. This review summarizes the current state of biologic therapies for esophageal, esophagogastric, and gastric malignancies, including those that target human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), c-Met, mechanistic target of rapamycin (mTOR) and immunomodulators. We focus primarily on agents that have been included in phase II and III clinical trials in locally advanced, progressive, or metastatic esophageal and gastric malignancies. At this time, only two biologic therapies are recommended by the National Comprehensive Cancer Network (NCCN): trastuzumab for patients with esophageal/esophagogastric or gastric adenocarcinomas with HER2 overexpression and ramucirumab, a VEGFR-2 inhibitor, as a second-line therapy for metastatic disease. However, recent reports of increases in overall and progression-free survival for agents including pertuzumab, apatinib, and pembrolizumab will likely increase the use of targeted biologic therapy in clinical practice for esophageal and gastric malignancies.
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Affiliation(s)
- Pamela Samson
- Division of Cardiothoracic Surgery, Washington University in St. Louis, St. Louis, MO, USA
| | - A. Craig Lockhart
- Division of Oncology, Washington University in St. Louis, St. Louis, MO, USA
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Press MF, Ellis CE, Gagnon RC, Grob TJ, Buyse M, Villalobos I, Liang Z, Wu S, Bang YJ, Qin SK, Chung HC, Xu J, Park JO, Jeziorski K, Afenjar K, Ma Y, Estrada MC, Robinson DM, Scherer SJ, Sauter G, Hecht JR, Slamon DJ. HER2 Status in Advanced or Metastatic Gastric, Esophageal, or Gastroesophageal Adenocarcinoma for Entry to the TRIO-013/LOGiC Trial of Lapatinib. Mol Cancer Ther 2017; 16:228-238. [PMID: 27811012 DOI: 10.1158/1535-7163.mct-15-0887] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Revised: 09/12/2016] [Accepted: 10/06/2016] [Indexed: 11/16/2022]
Abstract
HER2/ERBB2 status is used to select patients for HER2-targeted therapy. HER2/ERBB2 amplification/overexpression of upper gastrointestinal (UGI) adenocarcinomas was determined locally or in two central laboratories to select patients for the TRIO-013/LOGiC trial of chemotherapy with or without lapatinib. Patients selected locally had central laboratory confirmation of HER2 amplification for inclusion in the primary efficacy population. HER2 was assessed with PathVysion or IQ PharmDx FISH and HercepTest immunohistochemistry assays. Associations with outcomes were retrospectively evaluated. Overall, HER2 status was determined in UGI cancers from 4,674 patients in a central laboratory for eligibility (1,995 cases) and for confirmation of local HER2 results (333 cases). Of 1,995 adenocarcinomas screened centrally, 322 (16.1%) had HER2-amplified disease with 29 (1.5%) showing HER2 genomic heterogeneity. Men and older patients had higher rates of amplification. Of 545 patients accrued to the trial (gastric, 87.3%; GEJ, 8.3% and esophageal cancer, 4.4%), 487 patients (89%) were centrally confirmed as having HER2-amplified disease. Concordance between central and local HER2 testing was 83%. Concordance between PathVysion and IQ PharmDx FISH assays was 99% and FISH in the two central laboratories was 95%. Lapatinib-treated Asian participants and those less than 60 years had significant improvement in progression-free survival (PFS), particularly among those whose cancers had 5.01-10.0 and >10.0-fold amplification of HER2 In conclusion, HER2 is commonly amplified in UGI adenocarcinomas with amplification highly correlated to overexpression, and HER2 amplification levels correlated with PFS. While HER2 genomic heterogeneity occurs, its prevalence is low. Mol Cancer Ther; 16(1); 228-38. ©2016 AACR.
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Affiliation(s)
- Michael F Press
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
| | | | | | - Tobias J Grob
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Marc Buyse
- International Drug Development Institute, Leuven, Belgium
| | - Ivonne Villalobos
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | - Zhiyong Liang
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, P.R. China
| | - Shafei Wu
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, P.R. China
| | - Yung-Jue Bang
- Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Shu-Kui Qin
- PLA Cancer Center, Nanjing Bayi Hospital, Jiangsu, China
| | - Hyun Cheol Chung
- Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Jianming Xu
- The Affiliated Hospital Cancer Center, Academy of Military Medical Sciences, Beijing, China
| | - Joon Oh Park
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Krzysztof Jeziorski
- Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland
| | | | - Yanling Ma
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | - Monica C Estrada
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | | | | | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - J Randolph Hecht
- Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Santa Monica, California
| | - Dennis J Slamon
- Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Santa Monica, California
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Madani SH, Rahmati A, Sadeghi E, Khazaei S, Sadeghi M, Payandeh M, Amirifard N. Survey of Her2-neu Expression and its Correlation with Histology of Gastric Carcinoma and Gastroesophageal Junction Adenocarcinoma. Asian Pac J Cancer Prev 2016; 16:7755-8. [PMID: 26625793 DOI: 10.7314/apjcp.2015.16.17.7755] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND There is increasing evidence that HER2-neu is an important biomarker in gastric carcinomas (GC) and gastroesophageal junction (GEJ) adenocarcinomas. The aim of this study was to evaluate HER2-neu expression and also some clinicopathological features of these neoplasms. MATERIALS AND METHODS We selected 211 paraffin-embedded blocks, 193 GC and 18 GEJ. Then 4 micron sections were prepared for staining with hematoxylin and eosin and also for IHC (Her2-neu). The Chi-square test was used for significance between expression of HER2-neu and clinicopathological parameters. RESULTS In patients with advanced cancer of GC and GEJ, HER2-neu overexpression was more associated with the intestinal cancer subtype. CONCLUSIONS This could be a guide to new complementary therapy for affected patients.
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Affiliation(s)
- Seyed-Hamid Madani
- Molecular Pathology Research Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran E-mail :
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45
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Concordance of HER2 expression in paired primary and metastatic sites of gastric and gastro-oesophageal junction cancers. Pathology 2016; 47:641-6. [PMID: 26517644 DOI: 10.1097/pat.0000000000000323] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
HER2 is amplified/overexpressed in a subset of gastric and gastro-oesophageal junction cancers. Addition of anti-HER2 therapy has been shown to provide survival benefit in this setting. However, there are limited data assessing the concordance of HER2 status between primary and metastatic sites.A total of 113 samples from 43 paired primary and metastatic tumours were tested for HER2 status, by immunohistochemistry (IHC) for protein expression and silver in situ hybridisation (SISH) for gene amplification.Primary sites tested included endoscopic biopsies (n = 30) and resections (n = 24). Metastatic samples included lymph nodes (n = 29), peritoneal effusions (n = 21) and miscellaneous sites (n = 9). The overall HER2+ rate was 11%. Of 41 (95%; 95% CI 88.5-100%) concordant cases, 38 were HER2- and three were HER2+. There were two (5%) discordant cases, one of which showed heterogeneity of HER2 expression.This series confirms a high concordance rate of 95%, supporting that testing of primary tumours and metastases is equally valid and providing clinical rationale for the addition of anti-HER2 therapy in HER2+ disseminated disease.
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46
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Chan E, Duckworth LV, Alkhasawneh A, Toro TZ, Lu X, Ben-David K, Hughes SJ, Rossidis G, Zlotecki R, Lightsey J, Daily KC, Dang L, Allegra CJ, King B, George TJ. Discordant HER2 expression and response to neoadjuvant chemoradiotherapy in esophagogastric adenocarcinoma. J Gastrointest Oncol 2016; 7:173-80. [PMID: 27034783 PMCID: PMC4783750 DOI: 10.3978/j.issn.2078-6891.2015.071] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Accepted: 06/05/2015] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Targeting human epidermal growth factor receptor 2 (HER2) with trastuzumab in metastatic esophagogastric adenocarcinoma (EGA) improves survival. The impact of HER2 inhibition in combination with chemoradiotherapy (CRT) in early stage EGA is under investigation. This study analyzed the pattern of HER2 overexpression in matched-pair tumor samples of patients who underwent neoadjuvant CRT followed by surgery. METHODS All patients with EGA who underwent standard neoadjuvant CRT followed by esophagectomy at the University of Florida were included. Demographics, risk factors, tumor features, and outcome data were analyzed. Descriptive statistics, Chi-square exact test, uni- and multivariate analyses, and Kaplan Meier method were used. HER2 expression determined by immunohistochemical (IHC) was scored as negative (0, 1+), indeterminate (2+) or positive (3+). RESULTS Among 49 sequential patients (41 M/8 F) with matched-pair tumor samples, 9/49 patients (18%) had pathologic complete response (pCR), 10/49 had near pCR or not enough tumor (NET) to examine in the post- treatment samples. Patients with initial HER2 negativity demonstrated conversion to HER2 positivity after neoadjuvant CRT (7/30 cases; 23%). Baseline HER2 overexpression was more common in lower stage/node negative patients (67% in stages I, IIA vs. 33% in stages IIB, III) and did not correlate with treatment response or survival. CONCLUSIONS Although limited by a relatively small sample size, our study failed to demonstrate that baseline HER2 protein over-expression in EGA predicts response to standard CRT. However, our data suggested that HER2 was up regulated by CRT resulting in unreliable concordance between pre-treatment (pre-tx) and post-treatment (post-tx) samples. Pre-therapy HER2 expression may not reliably reflect the HER2 status of persistent or recurrent disease.
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47
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Jackie Oh S, Han S, Lee W, Lockhart AC. Emerging immunotherapy for the treatment of esophageal cancer. Expert Opin Investig Drugs 2016; 25:667-77. [DOI: 10.1517/13543784.2016.1163336] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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48
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Xu YP, Lin G, Sun XJ, Yan MH, Zhang G, Hu JL, Sun WY, Yu JM. C-Met as a Molecular Marker for Esophageal Squamous Cell Carcinoma and Its Association with Clinical Outcome. J Cancer 2016; 7:587-94. [PMID: 27053957 PMCID: PMC4820735 DOI: 10.7150/jca.13687] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Accepted: 01/09/2016] [Indexed: 12/12/2022] Open
Abstract
Background: Epidermal growth factor receptor (EGFR), c-Met, and human epidermal growth factor receptor 2 (HER2) are overexpressed in a variety of human cancers, and may serve as biomarkers for disease prognosis. We examined whether high expression of these molecular markers correlates with poor disease prognosis in esophageal squamous cell cancer (ESCC). Materials and Methods: Expression of EGFR, c-Met, and HER2 protein was detected by immunohistochemistry (IHC) in 180 paraffin-embedded tissue samples from stage IIB-IIIC ESCC patients. The overall survival (OS) rates were calculated according to the Kaplan-Meier method, and the log-rank test was used to evaluate differences between survival curves. The Cox proportional hazards model was used for univariate and multivariate analyses. Results: The median survival of all patients was 46 months. There was no significant difference in OS in terms of HER2 and EGFR status (P = 0.177 and P=0.061, respectively). However, there was a significant difference in OS between c-Met high expression patients and c-Met low expression or negative patients (median: 41.9 months vs. 56.7 months; P = 0.001). Multivariate analysis also showed that, of the covariates analyzed, c-Met high expression was the only prognostic factor for OS (HR: 0.459 [95 % confidence interval: 0.287-0.733]; P = 0.001). Patients with ESCC that had concurrent overexpression of EGFR and c-Met had significantly worse survival than ESCC that displayed overexpression of either EGFR or c-Met individually or that did not have overexpression of either protein (P=0.000). Conclusions: Overexpression of HER2 and EGFR individually is not significantly associated with poor prognosis in ESCC. High expression of c-Met may be indicative of a poorer prognosis in ESCC. In order to promote efficient and rapid development of therapeutic methods in ESCC, further studies are necessary to explore the role of c-Met.
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Affiliation(s)
- Ya-Ping Xu
- 1. School of Medicine, Shandong University, Jinan, China;; 2. Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, China
| | - Gang Lin
- 3. First Clinical Medical School, Wenzhou Medical University, Wenzhou, China
| | - Xiao-Jiang Sun
- 2. Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, China
| | - Mao-Hui Yan
- 2. Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, China
| | - Gu Zhang
- 4. Department of Pathology, Zhejiang Cancer Hospital, Hangzhou, China
| | - Jin-Lin Hu
- 4. Department of Pathology, Zhejiang Cancer Hospital, Hangzhou, China
| | - Wen-Yong Sun
- 4. Department of Pathology, Zhejiang Cancer Hospital, Hangzhou, China
| | - Jin-Ming Yu
- 5. Department of Radiation Oncology, Shandong University Affiliated Shandong Cancer Hospital and Institute, Jinan, Shandong, China
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49
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Huang D, Duan H, Huang H, Tong X, Han Y, Ru G, Qu L, Shou C, Zhao Z. Cisplatin resistance in gastric cancer cells is associated with HER2 upregulation-induced epithelial-mesenchymal transition. Sci Rep 2016; 6:20502. [PMID: 26846307 PMCID: PMC4742832 DOI: 10.1038/srep20502] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Accepted: 01/05/2016] [Indexed: 12/13/2022] Open
Abstract
Cisplatin remains to be primary chemotherapeutic drug for gastric cancer patients, especially for advanced stage ones. However, primary or acquired resistance often occurs with the mechanisms being not well understood, which results in relapse of the cancer and poor survival. Herein, we found that HER2 upregulation was associated with cisplatin resistance. We observed that cisplatin-resistant gastric cancer cells underwent a morphological change similar to epithelial-mesenchymal transition (EMT) which is mediated by HER2 overexpression. When specific monoclonal antibody Herceptin, small molecular targeted drug CP724714, or small interfering RNA against HER2 was applied, the EMT-like phenotypic change was dramatically reversed. More importantly, the IC50 and Resistance Index of resistant gastric cancer cells to cisplatin were also decreased by any of these treatments.We demonstrated that expression and amplification of HER2 positively correlated with expression of EMT-related transcription factor Snail in gastric cancer tissues. Furthermore, for the first time, we found that HER2/Snail double positive gastric cancer patients had poorer survival than single positive or double negative counterparts, which provided experimental evidence for the necessity of HER2/Snail double testing in gastric cancer. In conclusion, this study provides some clues of the association of cisplatin resistance with HER2 upregulation-induced EMT in gastric cancer cells.
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Affiliation(s)
- Dongsheng Huang
- Clinical Research Institute, Zhejiang Provincial People's Hospital, 158 Shangtang Road, Hangzhou 310014, China
| | - Hongying Duan
- Clinical Research Institute, Zhejiang Provincial People's Hospital, 158 Shangtang Road, Hangzhou 310014, China.,Department of Pathology, Zhejiang Provincial People's Hospital, 158 Shangtang Road, Hangzhou 310014, China
| | - Hao Huang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital &Institute, Beijing 100142, China
| | - Xiangmin Tong
- Clinical Research Institute, Zhejiang Provincial People's Hospital, 158 Shangtang Road, Hangzhou 310014, China
| | - Yong Han
- Department of Pathology, Zhejiang Provincial People's Hospital, 158 Shangtang Road, Hangzhou 310014, China
| | - Guoqing Ru
- Department of Pathology, Zhejiang Provincial People's Hospital, 158 Shangtang Road, Hangzhou 310014, China
| | - Like Qu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital &Institute, Beijing 100142, China
| | - Chengchao Shou
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital &Institute, Beijing 100142, China
| | - Zhongsheng Zhao
- Department of Pathology, Zhejiang Provincial People's Hospital, 158 Shangtang Road, Hangzhou 310014, China
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50
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Lasorsa A, Losacco M, Iacobazzi RM, Porcelli L, Azzariti A, Natile G, Arnesano F. Probing the interaction between cisplatin and the therapeutic monoclonal antibody trastuzumab. RSC Adv 2016. [DOI: 10.1039/c6ra04337b] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Cisplatin binds to the monoclonal antibody trastuzumab preferentially to the Fc fragment, leaving the antigen binding region unaffected. The two drugs are co-administered in cancer therapy.
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Affiliation(s)
- Alessia Lasorsa
- Department of Chemistry
- University of Bari “Aldo Moro”
- 70125 Bari
- Italy
| | - Maurizio Losacco
- Department of Chemistry
- University of Bari “Aldo Moro”
- 70125 Bari
- Italy
| | - Rosa Maria Iacobazzi
- Department of Pharmacy-Drug Sciences
- University of Bari “Aldo Moro”
- 70125 Bari
- Italy
- Istituto Tumori IRCCS Giovanni Paolo II
| | | | | | - Giovanni Natile
- Department of Chemistry
- University of Bari “Aldo Moro”
- 70125 Bari
- Italy
| | - Fabio Arnesano
- Department of Chemistry
- University of Bari “Aldo Moro”
- 70125 Bari
- Italy
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